Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)

Progress in Lipid Research

Volumn 48, Issue 1, 2009, Pages 1-26

  Musso, Giovanni ^a   Gambino, Roberto ^b   Cassader, Maurizio ^b  

^a GRADENIGO HOSPITAL   (Italy)

^b UNIVERSITY OF TURIN   (Italy)

Author keywords

Endocannabinoids; Fatty acid transport protein; Kinetics; Lipogenesis; Nuclear receptors; Oxidative stress; VLDL secretion

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; ACETYL COENZYME A CARBOXYLASE 1; ACETYL COENZYME A CARBOXYLASE 2; ACYL COENZYME A DESATURASE; BINDING PROTEIN; CARBOHYDRATE RESPONSIVE ELEMENT BINDING PROTEIN; CAVEOLIN; CD36 ANTIGEN; DIACYLGLYCEROL ACYLTRANSFERASE; DIACYLGLYCEROL ACYLTRANSFERASE 1; DIACYLGLYCEROL ACYLTRANSFERASE 2; ENDOCANNABINOID; FARNESOID X RECEPTOR; FATTY ACID BINDING PROTEIN; FATTY ACID SYNTHASE; FATTY ACID TRANSPORTER; LIVER X RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PREGNANE X RECEPTOR; STEAROYL COENZYME A DESATURASE 1; STEROL REGULATORY ELEMENT BINDING PROTEIN; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN;

CRYSTAL STRUCTURE; ENZYME ACTIVITY; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; FATTY ACID TRANSPORT; FATTY LIVER; HUMAN; INSULIN SENSITIVITY; LIPID LIVER LEVEL; LIPID METABOLISM; LIPID RAFT; LIPID STORAGE; LIPOGENESIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OXIDATIVE STRESS; PHENOTYPE; PHOSPHOLIPID METABOLISM; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; FATTY ACIDS; FATTY LIVER; HUMANS; KINETICS; LIPID METABOLISM; LIPOGENESIS; LIVER;

EID: 57649214103     PISSN: 01637827     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.plipres.2008.08.001     Document Type: Review

References (366)

1. Musso G., Gambino R., De Michieli F., et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37 (2003) 909-916
2. Musso G., Gambino R., Bo S., et al. Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A cross-sectional comparison with adult treatment Panel III criteria in nonobese nondiabetic subjects. Diabetes Care 31 (2008) 562-568
3. Farrell G.C., and Larter C.Z. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43 2 Suppl 1 (2006) S99-S112
4. Chitturi S., and Farrell G.C. Fatty liver now, diabetes and heart attack later? The liver as a barometer of metabolic health. J Gastroen Hepatol 22 (2007) 967-969
5. Donnelly K.L., Smith C.J., Schwarzenberg S.J., Jessurun J., Boldt M.D., and Parks E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115 (2005) 1343-1351
6. Timlin M.T., and Parks E.J. The temporal pattern of de novo lipogenesis in the postprandial state. Am J Clin Nutr 81 (2005) 35-42
7. Diraison F., Moulin P., and Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab 29 (2003) 478-485
8. Barrows B.R., and Parks E.J. Contributions of different fatty acid sources to very low-density lipoprotein-Triacylglycerol in the fasted and fed states. J Clin Endocrinol Metab 91 (2006) 1446-1452
9. Charlton M., Sreekumar R., Rasmussen D., et al. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 35 (2002) 898-904
10. Fabbrini E., Mohammed B.S., Magkos F., Korenblat K.M., Patterson B.W., and Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134 (2008) 424-431
11. Ravikumar B., Carey P.E., Snaar J.E., et al. Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes. Am J Physiol Endocrinol Metab 288 (2005) E789-E797
12. Heeren J., Niemeier A., Merkel M., et al. Endothelial-derived lipoprotein lipase is bound to postprandial triglyceride-rich lipoproteins and mediates their hepatic clearance in vivo. J Mol Med 80 (2002) 576-584
13. Merkel M., Weinstock P.H., Chajek-Shaul T., et al. Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia. J Clin Invest 102 (1998) 893-901
14. Stremmel W., Pohl L., Ring A., and Herrman T. A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids. Lipids 36 (2001) 981-989
15. Ehehalt R., Fullekrug J., Pohl J., et al. Translocation of long chain fatty acids across the plasma membrane - lipid rafts and fatty acid transport proteins. Mol Cell Biochem 284 (2006) 135-140
16. Pohl J., Ring A., Hermann T., et al. Role of FATP in parenchymal cell fatty acid uptake. Biochim Biophys Acta 1686 (2004) 1-6
17. Pohl J., Ring A., Ehehalt R., et al. New concepts of cellular fatty acid uptake: role of fatty acid transport proteins and of caveolae. Proc Nutr Soc 63 (2004) 259-262
18. Bradbury M.W., and Berk P.D. Lipid metabolism in hepatic steatosis. Clin Liver Dis 8 (2004) 639-671
19. Stump D.D., Nunes R.M., Sorrention D., Isola L.M., and Berk P.D. Characteristics of oleate binding to liver plasma membranes and its uptake by isolated hepatocytes. J Hepatol 16 (2002) 304-315
20. Rajaraman G., Roberts M.S., Hung D., Wang G.Q., and Burczynski F.J. Membrane binding proteins are the major determinants for the hepatocellular transmembrane flux of long-chain fatty acids bound to albumin. Pharm Res 22 (2005) 1793-1803
21. Daniel E.E., El-Yazbi A., and Cho W.J. Caveolae and calcium handling, a review and a hypothesis. J Cell Mol Med 10 (2006) 444-529
22. Fernandez M.A., Albor C., Ingelmo-Torres M., et al. Caveolin-1 is essential for liver regeneration. Science 313 (2006) 1628-1632
23. Pol A., Martin S., Fernandez M.A., et al. Dynamic and regulated association of caveolin with lipid bodies: modulation of lipid body motility and function by a dominant negative mutant. Mol Biol Cell 15 (2004) 99-110
24. Razani B., Combs T.P., Wang X.B., Frank P.G., Park D.S., Russell R.G., et al. Caveolin-1 deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem 277 (2002) 8635-8647
25. Doege H., and Stahl A. Protein-mediated fatty acid uptake: novel insights from in vivo models. Physiology (Bethesda) 21 (2006) 259-268
26. Stahl A. A current review of fatty acid transport proteins (SLC27). Pflug Arch 447 (2004) 722-727
27. Hall A.M., Wiczer B.M., Herrmann T., et al. Enzymatic properties of purified murine fatty acid transport protein 4 and analysis of acyl-CoA synthetase activities in tissues from FATP4 null mice. J Biol Chem 280 (2005) 11948-11954
28. Zou Z., DiRusso C.C., Ctrnacta V., and Black P.N. Fatty acid transport in Saccharomyces cerevisiae. Directed mutagenesis of FAT1 distinguishes the biochemical activities associated with Fat1p. J Biol Chem 277 (2002) 31062-31071
29. Schaiff W.T., Bildirici I., Cheong M., et al. Peroxisome proliferator-activated receptor-gamma and retinoid X receptor signaling regulate fatty acid uptake by primary human placental trophoblasts. J Clin Endocrinol Metab 90 (2005) 4267-4275
30. Gertow K., Rosell M., Sjogren P., et al. Fatty acid handling protein expression in adipose tissue, fatty acid composition of adipose tissue and serum, and markers of insulin resistance. Eur J Clin Nutr 60 (2006) 1406-1413
31. Doege H., Baillie R.A., Ortegon A.M., et al. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology 130 (2006) 1245-1258
32. Hubbard B., Doege H., Punreddy S., et al. Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity. Gastroenterology 130 (2006) 1259-1269
33. Glatz J.F.C., and Storch J. Unraveling the significance of cellular fatty acid-binding proteins. Curr Opin Lipidol 12 (2001) 267-274
34. Dyck D.J., Steinberg G., and Bonen A. Insulin increases FFA uptake and esterification but reduces lipid utilization in isolated contracting muscle. Am J Physiol Endocrinol Metab 281 (2001) E600-E607
35. Koonen D.P., Glatz J.F., Bonen A., and Luiken J.J. Long chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochim Biophys Acta 1736 (2005) 163-180
36. Luiken J.J.F.P., Koonen D.P.Y., Willems J., et al. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes 51 (2002) 3113-3119
37. Bonen A., Luiken J.J., Arumugam Y., Glatz J.F., and Tandon N.N. Acute regulation of fatty acid uptake involves the cellular redistribution of fatty acid traslocase. J Biol Chem 275 (2000) 14501-14508
38. Febbraio M., and Silverstein R.L. CD36: implications in cardiovascular disease. Int J Biochem Cell Biol 39 (2007) 2012-2030
39. Goudriaan J.R., Dahlmans V.E.H., Teusink B., et al. CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice. J Lipid Res 44 (2003) 2270-2277
40. Febbraio M., Abumrad N.A., Hajjar D.P., Sharma K., Cheng W., Pearce S.F., et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J Biol Chem 274 (1999) 19055-19062
41. Hajri T., Han X.X., Bonen A., and Abumrad N.A. Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest 109 (2002) 1381-1389
42. Bradbury M.W. Lipid metabolism and liver inflammation. I. Hepatic fatty acid uptake: possible role in steatosis. Am J Physiol Gastrointest Liver Physiol 290 (2006) G194-G198
43. Lavoie J.M., and Gauthier M.S. Regulation of fat metabolism in the liver: link to non-alcoholic hepatic steatosis and impact of physical exercise. Cell Mol Life Sci 63 (2006) 1393-1409
44. Koonen D.P.Y., Jacobs R.L., Febbraio M., et al. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 56 (2007) 2863-2871
45. Luiken J.J.F.P., Arumugam Y., Dyck D.J., et al. Increased rates of fatty acid uptake and plasmalemmal fatty acid transporters in obese Zucker rats. J Biol Chem 276 (2001) 40567-40573
46. Zhou J., Febbraio M., Wada T., et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARγ in promoting steatosis. Gastroenterology 134 (2008) 556-567
47. Greco D., Kotronen A., Westerbacka J., et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 294 (2008) G1281-G1287
48. Febbraio M., Abumrad N.A., Hajjar D.P., et al. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J Biol Chem 274 (1999) 19055-19062
49. Gavrilova O., Haluzik M., Matsusue K., Cutson J.J., Johnson L., Dietz K.R., et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278 (2003) 34268-34276
50. Zhou J., Zhai Y., Mu Y., et al. A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway. J Biol Chem 281 (2006) 15013-15020
51. Makowski L., and Hotamisligil G.S. The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis. Curr Opin Lipidol 16 (2005) 538-543
52. Makowski L., and Hotamisligil G.S. Fatty acid binding proteins - the evolutionary crossroads of inflammatory and metabolic responses. J Nutr 134 (2004) 2464S-2468S
53. Coe N.R., and Bernlohr D.A. Physiological properties and functions of intracellular fatty acid-binding proteins. Biochim Biophys Acta 1391 (1998) 287-306
54. Tan N.S., Shaw N.S., Vinckenbosch N., et al. Selective cooperation between fatty acid binding proteins and peroxisome proliferators-activated receptors in regulating transcription. Mol Cell Biol 22 (2002) 5114-5127
55. Helledie T., Antonius M., Sorensen R.V., et al. Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm. J Lipid Res 41 (2000) 1740-1751
56. Wolfrum C., Borrmann C.M., Borchers T., and Spener F. Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha -and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc Natl Acad Sci USA 98 (2001) 2323-2328
57. Sacchettini J.C., Gordon J.I., and Banaszak L.J. Thestructure of crystalline Escherichia coli- derived rat intestinal fatty acid-binding protein at 2.5-A resolution. J Biol Chem 263 (1988) 5815-5819
58. Zimmerman A.W., and Veerkamp J.H. New insights into the structure and function of fatty acid-binding proteins. Cell Mol Life Sci 59 (2002) 1096-1116
59. Liou H.-L., Kahn P.C., and Storch J. Role of the helical domain in fatty acid transfer from adipocyte and heart fatty acid-binding proteins to membranes. J Biol Chem 277 (2002) 1806-1815
60. Humphreys P., McCarthy M., Tuomilehto J., et al. Chromosome 4q locus associated with insulin resistance in Pima. Indians Studies in three European NIDDM populations. Diabetes 43 (1994) 800-804
61. Weiss E.P., Brown M.D., Shuldiner A.R., and Hagberg J.M. Fatty acid binding protein-2 gene variants and insulin resistance: gene and gene-environment interaction effects. Physiol Genomics 10 (2002) 145-157
62. Galluzzi J.R., Cupples L.A., Otvos J.D., Wilson P.W., Schaefer E.J., and Ordovas J.M. Association of the A/T54 polymorphism in the intestinal fatty acid binding protein with variations in plasma lipids in the Framingham offspring study. Atherosclerosis 159 (2001) 417-424
63. Galluzzi J.R., Cupples L.A., Meigs J.B., Wilson P.W., Schaefer E.J., and Ordovas J.M. Framingham Offspring study. Association of the Ala54-Thr polymorphism in the intestinal fatty acid-binding protein with 2-h postchallenge insulin levels in the Framingham Offspring study. Diabetes Care 24 (2001) 1161-1166
64. Baier L.J., Sacchettini J.C., Knowler W.C., et al. An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance. J Clin Invest 95 (1995) 1281-1287
65. Levy E., Menard D., Delvin E., et al. The polymorphism at codon 54 of the FABP2 gene increases fat absorption in human intestinal explants. J Biol Chem 276 (2001) 39679-39684
66. Stan S., Lambert M., Delvin E., Paradis G., O'loughlin J., Hanley J.A., et al. Intestinal fatty acid binding protein and microsomal triglyceride transfer protein polymorphisms in French-Canadian youth. J Lipid Res 46 (2005) 320-327
67. Dworatzek P.D.N., Hegele R.A., and Wolever T.M.S. Postprandial lipemia in subjects with the threonine 54 variant of the fatty acid-binding protein 2 gene is dependent on the type of fat ingested. Am J Clin Nutr 79 (2004) 11110-11117
68. Tuncman G., Erbay E., Hom X., et al. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci USA 103 (2006) 6970-6975
69. Newberry E.P., Xie Y., Kennedy S.M., et al. Decreased hepatic riglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. J Biol Chem 278 (2003) 51664-51672
70. Newberry E.P., Xie Y., Kennedy S.M., et al. Protection against western diet-induced obesity and hepatic steatosis in liver fatty acid-binding protein knockout mice. Hepatology 44 (2006) 1191-1205
71. Maeda K., Cao H., Kono K., et al. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes. Cell Metabolism 1 (2005) 107-119
72. Cohen P., Miyazaki M., Socci N.D., Hagge-Greenberg A., Liedtke W., Soukas A.A., et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297 (2002) 240-243
73. Westerbacka J., Kolak M., Kiviluoto T., et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver on insulin-resistant subjects. Diabetes 56 (2007) 2759-2765
74. Furuhashi M., Tuncman G., Görgün C.Z., et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447 (2007) 959-965
75. Hoekstra M., Stitzinger M., van Wanrooij E.J.A., et al. Microarray analysis indicates an important role for FABP5 and putative novel FABPs on a Western-type diet. J Lipid Res 47 (2006) 2198-2207
76. Spann N.J., Kang S., Li A.C., et al. Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis. J Biol Chem 281 (2006) 33066-33077
77. Landrier J.F., Thomas C., Grober J., et al. Fatty acid-binding protein (L-FABP). Gene expression is peroxisome proliferator-activated receptor-α-dependent. J Biol Chem 279 (2004) 45512-45518
78. Ameen C., Edvardsson U., Ljungberg A., et al. Activation of peroxisome proliferator-activated. Receptor-α Increases the expression and activity of microsomal triglyceride transfer protein in the liver. J Biol Chem 280 (2005) 1224-1229
79. Diraison F., Yankah V., Letexier D., et al. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J Lipid Res 44 (2003) 846-853
80. Tamura S., and Shimomura I. Contribution of adipose tissue and de novo lipogenesis to non-alcoholic fatty liver disease. J Clin Invest 115 (2005) 1139-1142
81. Chen G., Liang G., Ou J., Goldstein J.L., and Brown M.S. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci USA 101 (2004) 11245-11250
82. Zamora-Valdes D., Ponciano-Rodriguez G., Chavez-Tapia N.C., and Mendez-Sanchez N. The endocannabinoid system in chronic liver disease. Ann Hepatol 4 (2005) 248-254
83. Brown M.S., and Goldstein J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89 (1997) 331-340
84. Hua X., Wu J., Goldstein J.L., Brown M.S., and Hobbs H.H. Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics 25 (1995) 667-673
85. Guillet-Deniau I., Mieulet V., Le Lay S., Achouri Y., Carre D., Girard J., et al. Sterol regulatory element binding protein-1c expression and action in rat muscles: insulin- like effects on the control of glycolytic and lipogenic enzymes and UCP3 gene expression. Diabetes 51 (2002) 1722-1728
86. Ducluzeau P.H., Perretti N., Laville M., Andreelli F., Vega N., Riou J.P., et al. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 50 (2001) 1134-1142
87. Shimomura I., Shimano H., Horton J.D., Goldstein J.L., and Brown M. Differential expression of exons1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 99 (1997) 838-845
88. Yang T., Espenshade P.J., Wright M.E., Yabe D., Gong Y., Aebersold R., et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110 (2002) 489-500
89. Brown M.S., and Goldstein J.L. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 96 (1999) 11041-11048
90. Kim J.B., Sarraf P., Wright M., Yao K.M., Mueller E., Solanes G., et al. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J Clin Invest 101 (1998) 1-9
91. Horton J.D., Bashmakov Y., Shimomura I., and Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA 95 (1998) 5987-5992
92. Commerford S.R., Peng L., Dube J.J., and O'Doherty R.M. In vivo regulation of SREBP-1c in skeletal muscle: effects of nutritional status, glucose, insulin, and leptin. Am J Physiol Regul Integr Comp Physiol 287 (2004) R218-R227
93. Azzout-Marniche D., Becard D., Guichard C., Foretz M., Ferre P., and Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 350 (2000) 389-393
94. Sewter C., Berger D., Considine R.V., Medina G., Rochford J., Ciaraldi T., et al. Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes 51 (2002) 1035-1041
95. Ducluzeau P.H., Perretti N., Laville M., Andreelli F., Vega N., Riou J.P., et al. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 50 (2001) 1134-1142
96. Azzout-Marniche D., Becard D., Guichard C., Foretz M., Ferre P., and Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 350 (2000) 389-393
97. Fleischmann M., and Iynedjian P.B. Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem J 349 (2000) 13-17
98. Foretz M., Pacot C., Dugail I., Lemarchand P., Guichard C., Le Liepvre X., et al. ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol 19 (1999) 3760-3768
99. Tomita K., Tamiya G., Ando S., Kitamura N., Koizumi H., Kato S., et al. AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res 29 12 Suppl (2005) 240S-2405S
100. Steffensen K.R., and Gustafsson J.A. Putative metabolic effects of the liver X receptor (LXR). Diabetes 53 Suppl 1 (2004) S36-S42
101. Janowski B.A., Grogan M.J., Jones S.A., Wisely G.B., Kliewer S.A., Corey E.J., et al. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci USA 96 (1999) 266-271
102. Zelcer N., and Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116 (2006) 607-614
103. Ulven S.M., Dalen K.T., Gustafsson J.A., and Nebb H.I. LXR is crucial in lipid metabolism. Prostag Leukotr Ess Fatty Acids 73 (2005) 59-63
104. Chen G., Liang G., Ou J., Goldstein J.L., and Brown M.S. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci USA 101 (2004) 11245-11250
105. Repa J.J., Liang G., Ou J., Bashmakov Y., Lobaccaro J.M., Shimomura I., et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14 (2000) 2819-2830
106. Peet D.J., Turley S.D., Ma W., Janowski B.A., Lobaccaro J.M., Hammer R.E., et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93 (1998) 693-704
107. Laffitte B.A., Chao L.C., Li J., Walczak R., Hummasti S., Joseph S.B., et al. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci USA 100 (2003) 5419-5424
108. Schultz J.R., Tu H., Luk A., Repa J.J., Medina J.C., Li L., et al. Role of LXRs in control of lipogenesis. Genes Dev 14 (2000) 2831-2838
109. Yoshikawa T., Shimano H., Amemiya-Kudo M., Yahagi N., Hasty A.H., Matsuzaka T., et al. Identification of liver X receptor- retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 21 (2001) 2991-3000
110. Shimomura I., Bashmakov Y., and Horton J.D. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 274 (1999) 30028-30032
111. Shimomura I., Matsuda M., Hammer R.E., Bashmakov Y., Brown M.S., and Goldstein J.L. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 6 (2000) 77-86
112. Sekiya M., Yahagi N., Matsuzaka T., et al. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology 38 (2003) 1529-1539
113. Teran-Garcia M., Adamson A.W., Yu G., et al. Polyunsaturated fatty acid suppression of fatty acid synthase (FASN): evidence for dietary modulation of NF-Y binding to the Fasn promoter by SREBP-1c. Biochem J 402 (2007) 591-600
114. Kohjima M., Higuchi N., Kato M., Kotoh K., Yoshimoto T., Fujino T., et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med 21 (2008) 507-511
115. You M., and Crabb D.W. Molecular mechanisms of alcoholic fatty liver: role of sterol regulatory element-binding proteins. Alcohol 34 1 (2004) 39-43
116. Wang D., Wei Y., and Pagliassotti M.J. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147 (2006) 943-951
117. Werstuck G.H., Lentz S.R., Dayal S., et al. Homocysteine- induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest 107 (2001) 1263-1273
118. Puri P., Mirshahi F., Cheung O., et al. Activation and dysregulation of the unfolded protein response in nonalcoholic datty liver disease. Gastroenterology 134 (2008) 568-576
119. Esfandiari F., Villanueva J.A., Wong D.H., French S.W., and Halsted C.H. Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol 289 (2005) G54-G63
120. Schroder M., and Kaufman R.J. The mammalian unfolded protein response. Annu Rev Biochem 74 (2005) 739-789
121. Rutkowski D.T., and Kaufman R.J. A trip to the ER: coping with stress. Trends Cell Biol 14 (2004) 20-28
122. Ozcan U., Cao Q., Yilmaz E., et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306 (2004) 457-461
123. Zhou G., Myers R., Li Y., et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108 (2001) 1167-1174
124. Foretz M., Carling D., Guichard G., Ferré P., and Foufelle F. AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes. J Biol Chem 273 (1998) 14767-14771
125. Liang G., Yang J., Horton J.D., Hammer R.E., Goldstein J.L., and Brown M.S. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 277 (2002) 9520-9528
126. Decaux J.F., Antoine B., and Kahn A. Regulation of the expression of the L-type pyruvate kinase gene in adult rat hepatocytes in primary culture. J Biol Chem 264 (1989) 11584-11590
127. Stoeckman A.K., and Towle H.C. The role of SREBP-1c in nutritional regulation of lipogenic enzyme gene expression. J Biol Chem 277 (2002) 27029-27035
128. Uyeda K., and Repa J.J. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab 4 (2006) 107-110
129. Ishii S., Iizuka K., Miller B.C., and Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci USA 101 (2004) 15597-15602
130. Dentin R., Benhamed F., Pegorier J.P., et al. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J Clin Invest 115 (2005) 2843-2854
131. Dentin R., Pégorier J.P., Benhamed F., et al. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J Biol Chem 279 (2004) 20314-20326
132. Tsatsos N.G., and Towle H.C. Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism. Biochem Biophys Res Commun 340 (2006) 449-456
133. Li M.V., Chang B., Imamura M., Poungvarin N., and Chan L. Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module. Diabetes 55 (2006) 1179-1189
134. Ma L., Sham Y.Y., Walters K.J., and Towle H.C. A critical role for the loop region of the basic helix-loop-helix/leucine zipper protein mix in DNA binding and glucose-regulated transcription. Nucl Acids Res 35 (2006) 35-44
135. Cha J.Y., and Repa J.J. The Liver X receptor (LXR) and hepatic lipogenesis: the carbohydrate-response element-binding protein is a target gene of lxr. J Biol Chem 282 (2007) 743-751
136. Iizuka K., Bruick R.K., Liang G., Horton J.D., and Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci USA 101 (2004) 7281-7286
137. Dentin R., Girard J., and Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87 (2005) 81-86
138. Dentin R., Benhamed F., Hainault I., et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob. Mice Diabetes 55 (2006) 2159-2170
139. Morral N., Edenberg H.J., Witting S.R., Altomonte J., Chu T., and Brown M. Effects of glucose metabolism on regulation of genes of fatty acid synthesis and triglyceride secretion in the liver. J Lipid Res 48 (2007) 1499-1510
140. Lehmann J.M., Kliewer S.A., Moore L.B., et al. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272 (1997) 3137-3140
141. Mitro N., Mak P.A., Vargas L., Godio C., Hampton E., Molteni V., et al. The nuclear receptor LXR is a glucose sensor. Nature 445 (2007) 219-223
142. Auboeuf D., Rieusset J., Fajas L., et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 46 (1997) 1319-1327
143. Yoshikawa T., Shimano H., Amemiya-Kudo M., et al. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 21 (2001) 2991-3000
144. Joseph S.B., Laffitte B.A., Patel P.H., et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277 (2002) 11019-11025
145. Schultz J.R., Tu H., Luk A., et al. Role of LXRs in control of lipogenesis. Genes Dev 14 (2000) 2831-2838
146. Grefhorst A., Elzinga B.M., Voshol P.J., et al. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277 (2002) 34182-34190
147. Grefhorst A., van Dijk T.H., Hammer A., et al. Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice. Am J Physiol Endocrinol Metab 289 (2005) E829
148. Kotokorpi P., Ellis E., Parini P., Nilsson L.M., Strom S., Steffensen K.R., et al. Physiological differences between human and rat primary hepatocytes in response to liver X receptor activation by 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy] phenylacetic acid hydrochloride (GW3965). Mol. Pharmacol. 72 (2007) 947-955
149. Kase E.T., Thoresen G.H., Westerlund S., Hojlund K., Rustan A.C., and Gaster M. Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals. Diabetologia 50 (2007) 2171-2180
150. Blumberg B., Sabbagh W., Juguilon H., et al. SXR, a Novel steroid and Xenobiotic-sensing nuclear receptor. Genes Dev 12 (1998) 3195-3205
151. Xie W., Uppal H., Saini S.P., et al. Orphan nuclear receptor-mediated Xenobiotic regulation in drug metabolism. Drug Discov Today 9 (2004) 442-449
152. Bertilsson G., Heidrich J., Svensson K., et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 95 (1998) 12208-12213
153. Timsit Y.E., and Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 72 (2007) 231-246
154. Staudinger J.L., Goodwin B., Jones S.A., et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98 (2001) 3369-3374
155. Uppal H., Toma D., Saini S.P., Ren S., Jones T.J., and Xie W. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in Mice. Hepatology 41 (2005) 168-176
156. Bhalla S., Ozalp C., Fang S., Xiang L., and Kemper J.K. Ligand-activated Pregnane X receptor interferes with HNF-4 signaling by targeting a common coactivator PGC-1alpha. Functional implications in hepatic cholesterol and glucose metabolism. J Biol Chem 279 (2004) 45139-45147
157. Yoon J.C., Puigserver P., Chen G., et al. Control of Hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413 (2001) 131-138
158. Miao J., Fang S., Bae Y., and Kemper J.K. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. J Biol Chem 281 (2006) 14537-14546
159. Valenti L., Rametta R., Dongiovanni P., et al. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes 57 (2008) 1355-1362
160. Kodama S., Koike C., Negishi M., and Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Mol Cell Biol 24 (2004) 7931-7940
161. Tontonoz P., Nagy L., Alvarez J.G., Thomazy V.A., and Evans R.M. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93 (1998) 241-252
162. Wolfrum C., Asilmaz E., Luca E., Friedman J.M., and Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432 (2004) 1027-1032
163. Nakamura K., Moore R., Negishi M., and Sueyoshi T. Nuclear Pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver. J. Biol. Chem. 282 (2007) 9768-9776
164. Parks D.J., Blanchard S.G., Bledsoe R.K., et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 284 (1999) 1365-1368
165. Zhao A., Yu J., Lew J.L., Huang L., Wright S.D., and Cui J. Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol 23 (2004) 519-526
166. Nishimaki-Mogami T., Une M., Fujino T., Sato Y., Tamehiro N., Kawahara Y., et al. Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor. J Lipid Res 45 (2004) 1538-1545
167. Downes M., Verdecia M.A., Roecker A.J., et al. A Chemical, Genetic, and Structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11 (2003) 1079-1092
168. Laffitte B.A., Kast H.R., Nguyen C.M., Zavacki A.M., Moore D.D., and Edwards P.A. Identification of the DNA binding specificity and potential target genes for the farnesoid X-activated receptor. J Biol Chem 275 (2000) 10638-10647
169. Claudel T., Inoue Y., Barbier O., et al. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 125 (2003) 544-555
170. Savkur R.S., Thomas J.S., Bramlett K.S., Gao Y., Michael L.F., and Burris T.P. Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor gamma coactivator-1alpha. J Pharmacol Exp Ther 312 (2005) 170-178
171. Mi L.Z., Devarakonda S., Harp J.M., et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell 11 (2003) 1093-10100
172. Kalaany N.Y., and Mangelsdorf D.J. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu. Rev. Physiol. 68 (2006) 159-191
173. Zhang Y., Castellani L.W., Sinal C.J., Gonzalez F.J., and Edwards P.A. Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 18 (2004) 157-169
174. Watanabe M., Houten S.M., Wang L., et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113 (2004) 1408-1418
175. Cariou B., van Harmelen K., Duran-Sandoval D., et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in Mice. J Biol Chem 281 (2006) 11039-11049
176. Sinal C.J., Tohkin M., Miyata M., Ward J.M., Lambert G., and Gonzalez F.J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102 (2000) 731-744
177. Buchwald H., Varco R.L., Matts J.P., et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the program on the surgical control of the hyperlipidemias (POSCH). N Engl J Med 323 (1990) 946-955
178. Fiorucci S., Antonelli E., Rizzo G., et al. The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127 (2004) 1497-1512
179. Fiorucci S., Rizzo G., Antonelli E., et al. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 314 (2005) 584-595
180. Maloney P.R., Parks D.J., Haffner C.D., et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43 (2000) 2971-2974
181. Bardot O., Aldridge T.C., Latruffe N., and Green S. PPAR-RXR heterodimer activates a peroxisome proliferators response element upstream of the bifunctional enzyme gene. Biochem Biophys Res Commun 192 (1993) 37-45
182. Feige J.N., Gelman L., Michalik L., et al. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Progr Lipis Res 45 (2006) 120-159
183. Kallwitz E.R., McLachlan A., and Cotler S.J. Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J Gastroenterol 14 (2008) 22-28
184. Yamauchi T., Kamon J., Ito Y., et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423 (2003) 762-769
185. Yoon M.J., Lee G.Y., Chung J.J., Ahn Y.H., Hong S.H., and Kim J.B. Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 55 (2006) 2562-2570
186. Reddy J.K., and Hashimoto T. Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21 (2001) 193-230
187. Louet J.F., Chatelain F., Decaux J.F., et al. Long-chain fatty acidsregulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway. Biochem J 354 (2001) 189-197
188. Hansmannel F., Clemencet M.C., Le Jossic-Corcos C., Osumi T., Latruffe N., and Nicolas-Frances V. Functional characterization of a peroxisome proliferator response-element located in the intron 3 of rat peroxisomal thiolase B gene. Biochem Biophys Res Commun 311 (2003) 149-155
189. Kersten S., Seydoux J., Peters J.M., Gonzalez F.J., Desvergne B., and Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 103 (1999) 1489-1498
190. Hashimoto T., Cook W.S., QI C., et al. Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 275 (2000) 28918-28928
191. Nagasawa T., Inada Y., Nakano S., et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 536 (2006) 182-191
192. Harano Y., Yasui K., Toyama T., et al. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver. Liver Int 26 (2006) 613-620
193. Lefebvre P., Chinetti G., Fruchart J.C., and Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116 (2006) 571-580
194. Tobin J.F., and Freedman L.P. Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy. Trends Endocrinol Metab 17 (2006) 284-290
195. Forman B.M., Chen J., and Evans R.M. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 94 (1997) 4312-4317
196. Ip E., Farrell G., Hall P., Robertson G., and Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 39 (2004) 1286-1296
197. Palmer C.N., Hsu M.H., Griffin K.J., Raucy J.L., and Johnson E.F. Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol 53 (1998) 14-22
198. Lambe K.G., Woodyatt N.J., Macdonald N., Chevalier S., and Roberts R.A. Species differences in sequence and activity of the peroxisome proliferator response element (PPRE) within the acyl CoA oxidase gene promoter. Toxicol Lett 110 (1999) 119-127
199. Frick M.H., Elo O., Haapa K., et al. Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317 (1987) 1237-1245
200. Nakamuta M., Morizono S., Soejima Y., et al. Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation. Transplantation 80 (2005) 608-612
201. Nakano S., Inada Y., Masuzaki H., et al. Bezafibrate regulates the expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 292 (2007) E1213-E1222
202. Willson T.M., Brown P.J., Sternbach D.D., and Henke B.R. The PPARs: from orphan receptors to drug discovery. J Med Chem 43 (2000) 527-550
203. Basaranoglu M., Acbay O., and Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 31 (1999) 384
204. Athyros V.G., Mikhailidis D.P., Didangelos T.P., et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 22 (2006) 873-883
205. Laurin J., Lindor K.D., Crippin J.S., et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23 (1996) 1464-1546
206. Nakatani T., Katsumata A., Miura S., Kamei Y., and Ezaki O. Effects of fish oil feeding and fasting on LXRalpha/RXRalpha binding to LXRE in the SREBP-1c promoter in mouse liver. Biochim Biophys Acta 1736 (2005) 77-86
207. Alwayn I.P., Andersson C., Zauscher B., Gura K., Nose V., and Puder M. Omega-3 fatty acids improve hepatic steatosis in a murine model: potential implications for the marginal steatotic liver donor. Transplantation 79 (2005) 606-608
208. Hatzitolios A., Savopoulos C., Lazaraki G., et al. Efficacy of omega-3 fatty acids, atorvastatin and orlistat in non-alcoholic fatty liver disease with dyslipidemia. Indian J Gastroenterol 23 (2004) 131-134
209. Capanni M., Calella F., Biagini M.R., et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 23 (2006) 1143-1151
210. Rivellese A.A., Maffettone A., Iovine C., et al. Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 19 (1996) 1207-1213
211. Mori T.A., Bao D.Q., Burke V., Puddey I.B., Watts G.F., and Beilin L.J. Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr 70 (1999) 817-825
212. Savage D.B., Tan G.D., Acerini C.L., et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 52 (2003) 910-917
213. Gavrilova O., Haluzik M., Matsusue K., et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278 (2003) 34268-34276
214. Matsusue K., Haluzik M., Lambert G., et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 111 (2003) 737-747
215. Yang W.S., Jeng C.Y., Wu T.J., et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25 (2002) 376-380
216. Sun X., Han R., Wang Z., and Chen Y. Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Diabetologia 49 (2006) 1303-1310
217. Marra F., Efsen E., Romanelli R.G., et al. Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119 (2000) 466-478
218. Hazra S., Xiong S., Wang J., et al. Peroxisome proliferators-activated receptor γ induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 279 (2004) 11392-11401
219. She H., Xiong S., Hazra S., and Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem 280 (2005) 4959-4967
220. Miyazaki Y., Mahankali A., Matsuda M., et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 87 (2002) 2784-2791
221. Promrat K., Lutchman G., Uwaifo G.I., et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39 (2004) 188-196
222. Maeda N., Takahashi M., Funahashi T., et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50 (2001) 2094-2099
223. Yamauchi T., Kamon J., Ito Y., et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423 (2003) 762-769
224. Hardie D.G. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144 (2003) 5179-5183
225. Minokoshi Y., Kim Y.B., Peroni O.D., et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415 (2002) 339-343
226. Neuschwander-Tetri B.A., Brunt E.M., Wehmeier K.R., Oliver D., and Bacon B.R. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38 (2003) 1008-1017
227. Belfort R., Harrison S.A., Brown K., et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355 (2006) 2297-2307
228. Sanyal A.J., Mofrad P.S., Contos M.J., et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2 (2004) 1107-1115
229. Home P.D., Pocock S.J., Beck-Nielsen H., et al. Rosiglitazone evaluated for cardiovascular outcomes-an interim analysis. N Engl J Med 357 (2007) 28-38
230. Nagasawa T., Inada Y., Nakano S., et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 536 (2006) 182-191
231. Barish G.D., Narkar V.A., and Evans R.M. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 116 (2006) 590-597
232. Pacher P., Bátkai S., and Kunos G. The endocannabinoid system as an emerging target for pharmacotherapy. Pharmacol Rev 58 (2006) 389-462
233. Freund T.F., Katona I., and Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 83 (2003) 1017-1066
234. Bátkai S., Járai Z., Wagner J.A., et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 7 (2001) 827-832
235. Gaskari S.A., Liu H., Moezi L., et al. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Brit J Pharmacol 146 (2005) 315-323
236. Bátkai S., Mukhopadhyay P., Harvey-White J., et al. Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am J Physiol Heart Circ Physiol 293 (2007) H1689-H1695
237. Ros J., Clària J., To-Figueras J., et al. Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat. Gastroenterology 122 (2002) 85-93
238. Julien B., Grenard P., Teixeira-Clerc F., et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128 (2005) 742-755
239. Teixeira-Clerc F., Julien B., Grenard P., et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 12 (2006) 672-676
240. Osei-Hyiaman D., DePetrillo M., Pacher P., et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 115 (2005) 1298-1305
241. Jeong WI, Osei-Hyiaman D, Park O, et al. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab. 7; in press.
242. Hézode C., Roudot-Thoraval F., Nguyen S., et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 42 (2005) 63-71
243. Gary-Bobo M., Elachouri G., et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 46 (2007) 122-129
244. Kunos G., and Gao B. Endocannabinoids, CB1 Receptors, and liver disease: hitting more than one bird with the same stone. Gastroenterology 134 (2008) 622-625
245. Hézode C., Zafrani E.S., Roudot-Thoraval F., et al. Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C. Gastroenterology 134 (2008) 432-439
246. Banasch M., Goetze O., Schmidt W.E., and Meier J.J. Rimonabant as a novel therapeutic option for nonalcoholic steatohepatitis. Liver Int 27 (2007) 1152-1155
247. Mendez-Sanchez N., Zamora-Valdes D., Pichardo-Bahena R., et al. Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease. Liver Int 27 (2007) 215-219
248. Artmann A., Petersen G., Hellgren L.I., et al. Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta 1781 (2008) 200-212
249. Liu J., Batkai S., Pacher P., et al. Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-kappa B independently of platelet-activating factor. J Biol Chem 278 (2003) 45034-45039
250. Cases S., Stone S.J., Zhou P., et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J Biol Chem 276 (2001) 38870-38876
251. Cases S., Smith S.J., Zheng Y.W., et al. Identification of a gene encoding an acyl CoA:diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci USA 95 (1998) 13018-13023
252. Stone S.J., Myers H.M., Watkins S.M., et al. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J Biol Chem 279 (2004) 11767-11776
253. Chen H.C., Smith S.J., Ladha Z., et al. Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 109 (2002) 1049-1055
254. Yu X.X., Murray S.F., Pandey S.K., et al. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 42 (2005) 362-371
255. Choi C.S., Savane D.B., Kulkarni A., et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 282 (2007) 22678-22688
256. Samuel V.T., Liu Z.X.‡., Qu X., et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279 (2004) 32345-32353
257. Samuel V.T., Liu Z.X., Wang A., et al. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 117 (2007) 737-745
258. Neschen S., Morino K., Hammond L.E., et al. Cell Metab 2 (2005) 55-65
259. Considine R.V., Nyce M.R., Allen L.E., et al. Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia. J Clin Invest 95 (1995) 2938-2944
260. Yu C., Chen Y., Cline G.W., et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277 (2002) 50230-50236
261. Yamaguchi K., Yang L., McCall S., et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with non-alcoholic steatohepatitis. Hepatology 45 (2007) 1366-1374
262. Wei Y., Wang D., and Pagliassotti M.J. Saturated fatty acid-mediated endoplasmic reticulum stress and apoptosis are augmented by trans-10, cis-12-conjugated linoleic acid in liver cells. Mol Cell Biochem 303 (2007) 105-113
263. Santangelo C., Matarrese P., Masella R., et al. Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress. J Mol Endocrinol. 38 (2007) 147-158
264. Malhi H., Bronk S.F., Werneburg N.W., and Gores G.J. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem 281 (2006) 12093-12101
265. Han M.S., Park S.Y., Shinzawa K., et al. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res 49 (2008) 84-97
266. Yen C.L., Monetti M., Burri B.J., and Farese R.V.J. The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J Lipid Res 46 (2005) 1502-1511
267. Yamaguchi K., Yang L., McCall S., et al. Diacylglycerol acyltransferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis. Hepatology 47 (2008) 625-635
268. Munday M.R. Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans 30 (2002) 1059-1064
269. Abu-Elheiga L., Matzuk M.M., Abo-Hashema K.A., and Wakil S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291 (2001) 2613-2616
270. Abu-Elheiga L., Brinkley W.R., Zhong L., Chirala S.S., Woldegiorgis G., and Wakil S.J. The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci USA 97 (2000) 1444-1449
271. Abu-Elheiga L., Matzuk M.M., Abo-Hashema K.A., and Wakil S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291 (2001) 2613-2616
272. Abu-Elheiga L., Matzuk M.M., Kordari P., et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci USA 102 (2005) 12011-12016
273. Savage D.B., Choi C.S., Samuel V.T., et al. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest. 116 (2006) 817-824
274. Frescas D., Valenti L., and Accili D. Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280 (2005) 20589-20595
275. Accili D., and Arden K.C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117 (2004) 421-426
276. Abu-Elheiga L., Oh W., Kordari P., and Wakil S.J. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat_high-carbohydrate diets. Proc. Natl Acad Sci USA 100 (2003) 10207-10212
277. Harwood Jr. H.J. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opin. Ther. Targets 9 (2005) 267-281
278. Miyazaki M., Kim Y.C., and Ntambi J.M. A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis. J Lipid Res 42 (2001) 1018-1024
279. Warensjo E., Riserus U., and Vessby B. Fatty acid composition of serum lipids predicts the development of the metabolic syndrome in men. Diabetologia 48 (2005) 1999-2005
280. Pan D.A., Lillioja S., Milner M.R., et al. Skeletal muscle membrane lipid composition is related to adiposity and insulin action. J Clin Invest 96 (1995) 2802-2808
281. Cohen P., Miyazaki M., Socci N.D., et al. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297 (2002) 240-243
282. Rahman S.M., Dobrzyn A., Dobrzyn P., Lee S.H., Miyazaki M., and Ntambi J.M. Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle. Proc Natl Acad Sci USA 100 (2003) 11110-11115
283. Dobrzyn P., Dobrzyn A., Miyazaki M., et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci USA 101 (2004) 6409-6414
284. Ntambi J.M., Miyazaki M., Stoehr J.P., et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA 99 (2002) 11482-11486
285. Jiang G., Li Z., Liu F., et al. Prevention of obesity in mice by antisense oligonucleotide inhibitors of stearoyl-CoA desaturase-1. J Clin Invest 115 (2005) 1030-1038
286. Gutiérrez-Juárez R., Pocai A., Mulas C., et al. Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance. J Clin Invest 116 (2006) 1686-1695
287. Miyazaki M., Flowers M.T., Sampath H., et al. Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. Cell Metab. 6 (2007) 484-496
288. Listenberger L.L., Han X., Lewis S.E., et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA 100 (2003) 3077-3082
289. Buettner R., Ottinger I., Scholmerich J., and Bollheimer L.C. Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 286 (2004) E828-E833
290. Monetti M., Levin M.C., Watt M.J., et al. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6 (2007) 69-78
291. Abu-Elheiga L., Matzuk M.M., Kordari P., et al. Mutant mice lacking acetyl-CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci USA 102 (2005) 12011-12016
292. Chakravarthy M.V., Pan Z., Zhu Y., et al. New hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 1 (2005) 309-322
293. Le May C., Caüzac M., Diradourian C., et al. Fatty acids induce L-CPT I gene expression through a PPARalpha-independent mechanism in rat hepatoma cells. J Nutr 135 (2005) 2313-2319
294. Fromenty B., Robin M.A., Igoudjil A., Mansouri A., and Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab 30 (2004) 121-138
295. Wei Y., Rector R.S., Thyfault J.P., and Ibdah J.A. Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroenterol 14 (2008) 193-199
296. Begriche K., Igoudjil, Pessayre D., and Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6 (2006) 1-28
297. Reddy J.K. Nonalcoholic steatosis and steatohepatitis III Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Physiol 281 (2001) G1333-G1339
298. MacDonald G.A., and Prins J.B. Peroxisomal fatty acid metabolism, peroxisomal proliferator-activated receptors and nonalcoholic fatty liver disease. J Gastroenterol Hepatol 19 (2004) 1335-1337
299. Reddy J.K., and Hashimoto T. Peroxisomal β-oxidation and peroxisome proliferator-activated receptor α: an adaptive metabolic system. Annu Rev Nutr 21 (2001) 193-230
300. Tolwani R.J., Hamm D.A., Tian L., et al. Medium chain acyl-CoA dehydrogenase deficiency in gene-targeted mice. Plos Genetics 1 (2005) 205-212
301. Fan C.Y., Pan J., Usuda N., Yeldandi A.V., Rao M.S., and Reddy J.K. Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. J Biol Chem 273 (1998) 15639-15645
302. Caldwell S.H., Swerdlow R.H., Khan E.M., et al. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 31 (1999) 430-434
303. Berson A., De Beco V., Lettéron P., et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 114 (1998) 764-774
304. Haque M., Mirshahi F., Campbell-Sargent C., Sterling R.K., Luketic V.A., and Shiffman V.A. Nonalcoholic steatohepatitis (NASH) is associated with hepatocyte mitochondrial DNA depletion. Hepatology 36 (2002) 403A
305. Perez-Carreras M., del Hoyo P., Martin M.A., et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38 (2003) 999-1007
306. Cortez-Pinto H., Chatham J., Chacko V.P., Arnold C., Rashid A., and Diehl A.M. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282 (1999) 1659-1664
307. Bergamini C.M., Gambetti S., Dondi A., and Cervellati C. Oxygen, reactive oxygen species and tissue damage. Curr Pharm Des 10 (2004) 1611-1626
308. Garcia-Ruiz C., Colell A., Morales A., Kaplowitz N., and Fernandez-Checa J.C. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-kappa B: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol 48 (1995) 825-834
309. Cortez-Pinto H., Zhi Lin H., Qi Yang S., Odwin D.A., Costa S., and Diehl A.M. Lipids up-regulate uncoupling protein 2 expression in rat hepatocytes. Gastroenterology 116 (1999) 1184-1193
310. Chen J., Schenker S., Frosto T.A., and Henderson G.I. Inhibition of cytochrome c oxidase activity by 4-hydroxynonenal (HNE). Role of HNE adduct formation with the enzyme subunits. Biochim Biophys Acta 1380 (1998) 336-344
311. Tomita K., Tamiya G., Ando S., et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 55 (2006) 415-424
312. Garcia-Ruiz I., Rodriguez-Juan C., Diaz-Sanjuan T., et al. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology 44 (2006) 581-591
313. Mannaerts G.P., Van Veldhoven P.P., and Casteels M. Peroxisomal lipid degradation via beta- and alpha-oxidation in mammals. Cell Biochem Biophys 32 (2000) 73-87
314. Hermesh O., Kalderon B., and Bar-Tana J. Mitochondria uncoupling by a long chain fatty acyl analogue. J Biol Chem 273 (1998) 3937-3942
315. Weltman M.D., Farrell G.C., Hall P., Ingelman-Sundberg M., and Liddle C. Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis. Hepatology 27 (1998) 128-133
316. Orellana M., Rodrigo R., Varela N., et al. Relationship between in vivo chlorzoxazone hydroxylation, hepatic cytochrome P450 2E1 content and liver injury in obese non-alcoholic fatty liver disease patients. Hepatol Res 34 (2006) 57-63
317. Chalasani N., Gorski J.C., and Asghar M.S. Hepatic cytochrome P450 2E1 activity in nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 37 (2003) 544-550
318. Leclercq I.A., Farrell G.C., Field J., Bell D.R., Gonzalez F.J., and Robertson G.R. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 105 (2000) 1067-1075
319. Fisher E.A., and Ginsberg H.N. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J Biol Chem 277 (2002) 17377-17380
320. Schmidtke G., Holzhutter H.G., Bogyo M., et al. How an inhibitor of the HIV-I protease modulates proteasome activity. J Biol Chem 274 (1999) 35734-35740
321. Pan M., Cederbaum A.I., Zhang Y.L., Ginsberg H.N., Williams K.J., and Fisher E.A. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J Clin Investig 113 (2004) 1277-1287
322. Williams K.J., and Fisher E.A. Atherosclerosis: cell biology and lipoproteins-three distinct processes that control apolipoprotein-B secretion. Curr Opin Lipidol 12 (2001) 235-237
323. Fisher E.A., Pan M., Chen X., et al. The triple threat to nascent apolipoprotein B. Evidence for multiple, distinct degradative pathways. J Biol Chem 276 (2001) 27855-27863
324. Verkade H.J., Fast D.G., Rusiñol A.E., Scraba D.G., and Vance D.E. Impaired biosynthesis of phosphatidylcholine causes a decrease in the number of very low density lipoprotein particles in the Golgi but not in the endoplasmic reticulum of rat liver. J Biol Chem 268 (1993) 24990-24996
325. Wang C.N., Hobman T.C., and Brindley D.N. Degradation of apolipoprotein B in cultured rat hepatocytes occurs in a post-endoplasmic reticulum compartment. J Biol Chem 270 (1995) 24924-24931
326. Brown A.M., and Gibbons G.F. Insulin inhibits the maturation phase of VLDL assembly via a phosphoinositide 3-kinase-mediated event. Arterioscl Thromb Vasc Biol 21 (2001) 1656-1661
327. Au W.S., Kung H.F., and Lin M.C. Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes 52 (2003) 1073-1080
328. Nassir F., Xie Y., Patterson B.W., Luo J., and Davidson N.O. Hepatic secretion of small lipoprotein particles in apobec-1-/- mice is regulated by the LDL receptor. J Lipid Res 45 (2004) 1649-1659
329. Blasiole D.A., Oler A.T., and Attie A.D. Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB. J Biol Chem 283 (2008) 11374-11381
330. Horton J.D., Shimano H., Hamilton R.L., Brown M.S., and Goldstein J.L. Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL. J Clin Invest 103 (1999) 1067-1076
331. Twisk J., Gillian-Daniel D.L., Tebon A., Wang L., Barrett P.H., and Attie A.D. The role of the LDL receptor in apolipoprotein B secretion. J Clin Invest 105 (2000) 521-532
332. Larsson S.L., Skogsberg J., and Bjokegren J. The low density lipoprotein receptor prevents secretion of dense apoB100-containing 0lipoproteins from the liver. J Biol Chem 279 (2004) 831-836
333. Chakravarthy M.V., Pan Z., Zhu Y., et al. New hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 1 (2005) 309-322
334. Zhang Y.L., Hernandez-Ono A., Ko C., Yasunaga K., Huang L.S., and Ginsberg H.N. Regulation of hepatic apolipoprotein B-lipoprotein assembly and secretion by the availability of fatty acids. I. Differential response to the delivery of fatty acids via albumin or remnant-like emulsion particles. J Biol Chem 279 (2004) 19362-19374
335. Yamasaki T., Sasaki E., Kakinuma C., et al. Increased VLDL secretion and gonadal fat mass in mice overexpressing DGAT. J Biol Chem 280 (2005) 21506-21514
336. Letteron P., Sutton A., Mansouri A., Fromenty B., and Pessayre D. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38 (2003) 133-140
337. Raabe M., Veniant M.M., Sullivan M.A., et al. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice. J Clin Invest 103 (1999) 1287-1298
338. Cuchel M., Bloedon L.T., Szapary P., et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 356 (2007) 148-156
339. Pan X., Hussain F.N., Iqbal J., et al. Inhibiting proteasomal degradation of microsomal triglyceride transfer protein prevents CCl4-induced steatosis. J Biol Chem 282 (2007) 17078-17089
340. Oliveira C.P., Alves V.A., Lima V.M., et al. Modulation of hepatic microsomal triglyceride transfer protein (MTP) induced by S-nitroso-N-acetylcysteine in ob/ob mice. Biochem Pharmacol 74 (2007) 290-297
341. Schonfeld G. Familial hypobetalipoproteinemia: a review. J Lipid Res 44 (2003) 878-883
342. Raabe M., Flynn L.M., Zlot C.H., et al. Knockout of the abetalipoproteinemia gene in mice: reduced lipoprotein secretion in heterozygotes and embryonic lethality in homozygotes. Proc Natl Acad Sci USA 95 (1998) 8686-8691
343. Bernard S., Touzet S., Personne I., et al. Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with type II diabetes. Diabetologia 43 (2000) 995-999
344. Namikawa C., Shu-Ping Z., Vyselaar J.R., et al. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 40 (2004) 781-786
345. Gambino R., Cassader M., Pagano G., Durazzo M., and Musso G. Polymorphisms in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH?. Hepatology 45 (2007) 1097-1107
346. Taghibiglou C., Carpentieri A., Van Iderstine S.C., et al. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. J Biol Chem 275 (2000) 8416-8425
347. Kohen Avramoglu R., Basciano H., and Adeli K. Lipid and lipoprotein dysregulation in insulin resistant states. Clinica Chimica Acta 368 (2006) 1-19
348. Botham K.M., Zheng X., Napolitano M., et al. The effects of dietary n-3 polyunsaturated fatty acids delivered in chylomicron remnants on the transcription of genes regulating synthesis and secretion of very-low-density lipoprotein by the liver: modulation by cellular oxidative state. Exp Biol Med 228 (2003) 143-151
349. Uchiyama S., Shimizu T., and Shirasawa T. CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice. J Biol Chem. 281 (2006) 31713-31719
350. Ota T., Gayet C., and Ginsberg H.N. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 118 (2008) 316-332
351. Jiang X.C., Li Z., Liu R., et al. Phospholipid Transfer Protein Deficiency Impairs Apolipoprotein-B Secretion from Hepatocytes by Stimulating a Proteolytic Pathway through a Relative Deficiency of Vitamin E and an Increase in Intracellular Oxidants. J Biol Chem 280 (2005) 18336-18340
352. Vance J.E., and Vance D.E. Metabolic insights into phospholipid function using gene-targeted mice. J Biol Chem 280 (2005) 10877-10880
353. Devaux P.F. Static and dynamic lipid asymmetry in cell membranes. Biochemistry 30 (1991) 1163-1173
354. Walkey C.J., Yu L., Agellon L.B., and Vance D.E. Biochemical and evolutionary significance of phospholipid methylation. J Biol Chem 273 (1998) 27043-27046
355. Zhu X., Song J., Mar M.H., Edwards L.J., and Zeisel S.H. Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic coline metabolite concentrations despite ingesting a recommended dietary intake of coline. Biochem J 370 (2003) 987-993
356. Noga A.A., and Vance D.E. A gender-specific role for phosphatidylethanolamine N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice. J Biol Chem 278 (2003) 21851-21859
357. Noga A.A., and Vance D.E. Insights into the requirement of phosphatidylcholine synthesis for liver function in mice. J Lipid Res 44 (2003) 1998-2005
358. Noga A.A., Zhao Y., and Vance D.E. An unexpected requirement for phosphatidylethanolamine N-methyltransferase in the secretion of very low density lipoproteins. J Biol Chem 277 (2002) 42358-42365
359. Yao Z.M., and Vance D.E. The active synthesis of phosphatidylcholine is required for very low density lipoprotein secretion from rat hepatocytes. J Biol Chem 263 (1988) 2998-3004
360. Zeisel S.H., daCosta K.A., Franklin P.D., Alexander E.A., Lamont J.T., Sheard N.F., et al. Choline, an essential nutrient for humans. FASEB J 5 (1991) 2093-2098
361. Buchman A., Dubin M., Moukarzel A., Jenden D., Roch M., Rice K., et al. Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22 (1995) 1399-1403
362. Song J., da Costa K.A., Fischer L.M., et al. Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J 19 10 (2005) 1266-1271
363. Dong H., Wang J., Li C., Hirose A., et al. The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol 46 (2007) 915-920
364. Romeo S., Cohen J.C., and Hobbs H.H. No association between polymorphism in PEMT (V175M) and hepatic triglyceride content in the Dallas heart study. FASEB J 20 (2006) 2180
365. Li Z., Agellon L.B., Allen T.M., et al. The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab. 3 (2006) 321-331
366. Choi C.S., Savage D.B., Kulkarni A., et al. Suppression od diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 282 (2007) 22678-22688