The mechanistic basis for the induction of hepatic steatosis by xenobiotics

Expert Opinion on Drug Metabolism and Toxicology

Volumn 7, Issue 8, 2011, Pages 949-965

  Amacher, David E ^a  

^a NONE   (United States)

Author keywords

hepatic steatosis; liver; mechanisms; xenobiotics

Indexed keywords

AMINEPTINE; AMIODARONE; BINDING PROTEIN; CARBOHYDRATE RESPONSIVE ELEMENT BINDING PROTEIN; CARNITINE PALMITOYLTRANSFERASE I; DOXYCYCLINE; FATTY ACID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LIPOPROTEIN; LIVER X RECEPTOR; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; PERHEXILINE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIRPROFEN; PREGNANE X RECEPTOR; SIRTUIN 1; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; TETRACYCLINE; TIANEPTINE; UNCLASSIFIED DRUG; VALPROIC ACID; XENOBIOTIC AGENT;

ADIPOSE TISSUE; ANGINA PECTORIS; DRUG MECHANISM; ENDOPLASMIC RETICULUM STRESS; EPILEPSY; FATTY ACID METABOLISM; FATTY LIVER; HEART ATRIUM FIBRILLATION; HUMAN; LIPID PEROXIDATION; LIPID STORAGE; LIPOGENESIS; LIVER CELL; LIVER CIRRHOSIS; LIVER DISEASE; LIVER FAILURE; LIVER FIBROSIS; LIVER METABOLISM; LIVER TOXICITY; MICROARRAY ANALYSIS; NEUROLOGICAL COMPLICATION; NONHUMAN; OXIDATIVE STRESS; PROTEIN PROTEIN INTERACTION; PROTEIN TRANSPORT; REVIEW; SINGLE DRUG DOSE;

EID: 79960542143     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2011.577740     Document Type: Review

References (133)

1. Zimmerman HJ. Hepatoxicity. The adverse effects of drugs and other chemicals on the liver. Lippincott Williams & Wilkins, Philadelphia; 1999. p. 61
2. Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J Hepatol 1997;26(Suppl 2):43-53
3. Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis 2010;9:42
4. Guzman M, Castro J. Zonation of fatty acid metabolism in rat liver. Biochem J 1989;264:107-13 (Pubitemid 19283508)
5. Tong L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci 2005;62:1784-803 (Pubitemid 41188519)
6. Wang D, Sul HS. Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J Biol Chem 1998;273:25420-6 (Pubitemid 28443310)
7. Mauvoisin D, Mounier C. Hormonal and nutritional regulation of SCD1 gene expression. Biochimie 2011;93:78-86
8. Vallim T, Salter AM. Regulation of hepatic gene expression by saturated fatty acids. Prostaglandins Leukot Essent Fatty Acids 2010;82(4-6):211-18
9. Harada N, Oda Z, Hara Y, et al. Hepatic de novo lipogenesis is present in liver-specific ACC1-deficient mice. Mol Cell Biol 2007;27:1881-8
10. Abu-Elheiga L, Brinkley WR, Zhong L, et al. The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci USA 2000;97:1444-9 (Pubitemid 30118460)
11. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 2004;114:147-52 (Pubitemid 39071617)
12. Bayascas JR. Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle 2008;7:2978-82
13. Cheng Z, Tseng Y, White MF. Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab 2010;2:589-98
14. Cheng Z, White MF. Targeting Forkhead box O1 from the concept to metabolic diseases: lessons from mouse models. Antioxid Redox Signal 2011;14:649-61
15. Kamagate A, Dong HH. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle 2008;7:3162-70
16. Porstmann T, Griffiths B, Chung YL, et al. PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene 2005;24:6465-81 (Pubitemid 41486630)
17. Denechaud PD, Girard J, Postic C. Carbohydrate responsive element binding protein and lipid homeostasis. Curr Opin Lipidol 2008;19:301-6 (Pubitemid 351681558)
18. Baranowski M. Biological role of liver X receptors. J Physiol Pharmacol 2008;59(Suppl 7):31-55
19. Iizuka K, Horikawa Y. ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J 2008;55:617-24
20. Rawson RB. Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs). Biochem Soc Symp 2003;70:221-31 (Pubitemid 38497228)
21. Yang T, Espenshade PJ, Wright ME, 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 2002;110:489-500 (Pubitemid 35232292)
22. Feramisco JD, Goldstein JL, Brown MS. Membrane topology of human insig-1, a protein regulator of lipid synthesis. J Biol Chem 2004;279:8487-96 (Pubitemid 38294742)
23. Konig B, Koch A, Spielmann J, et al. Activation of PPARalpha and PPARgamma reduces triacylglycerol synthesis in rat hepatoma cells by reduction of nuclear SREBP-1. Eur J Pharmacol 2009;605:23-30
24. Villanueva CJ, Monetti M, Shih M, et al. Specific role for acyl CoA: Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology 2009;50:434-42
25. Ringseis R, Muschick A, Eder K. Dietary oxidized fat prevents ethanol-induced triacylglycerol accumulation and increases expression of PPARalpha target genes in rat liver. J Nutr 2007;137:77-83 (Pubitemid 46052862)
26. You M, Liang X, Ajmo JM, Ness GC. Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 2008;294:G892-8 (Pubitemid 351520077)
27. You M, Rogers CQ. Adiponectin: a key adipokine in alcoholic fatty liver. Exp Biol Med (Maywood) 2009;234:850-9
28. Shen Z, Liang X, Rogers CQ, et al. Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2010;298:G364-74
29. Ge F, Zhou S, Hu C, et al. Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice. Am J Physiol Gastrointest Liver Physiol 2010;299:G855-66
30. Nishino M, Hayakawa K, Nakamura Y, et al. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol 2003;180:129-34 (Pubitemid 36008699)
31. Cole LK, Jacobs RL, Vance DE. Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology 2010;52:1258-65
32. Wang YM, Hu XQ, Xue Y, et al. Study on possible mechanism of orotic acid-induced fatty liver in rats. Nutrition 2010; published online 16 December 2010 doi:10.1016/j.nut.2010.03.005
33. Hellerstein MK, Schwarz JM, Neese RA. Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr 1996;16:523-57 (Pubitemid 26286864)
34. Diraison F, Beylot M. Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. Am J Physiol 1998;274(2 Pt 1):E321-7
35. Foster DW. The role of the carnitine system in human metabolism. Ann NY Acad Sci 2004;1033:1-16 (Pubitemid 39656734)
36. Bonnefont JP, Djouadi F, Prip-Buus C, et al. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 2004;25:495-520 (Pubitemid 39195073)
37. Song S, Attia RR, Connaughton S, et al. Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements. Mol Cell Endocrinol 2010;325:54-63
38. van der Leij FR, Bloks VW, Grefhorst A, et al. Gene expression profiling in livers of mice after acute inhibition of beta-oxidation. Genomics 2007;90:680-9 (Pubitemid 350176644)
39. Ruderman NB, Saha AK, Kraegen EW. Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity. Endocrinology 2003;144:5166-71 (Pubitemid 37476042)
40. Ruderman NB, Park H, Kaushik VK, et al. AMPK as a metabolic switch in rat muscle, liver and adipose tissue after exercise. Acta Physiol Scand 2003;178:435-42 (Pubitemid 36960435)
41. Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009;458:1056-60
42. Whitehead JP, Richards AA, Hickman IJ, et al. Adiponectin-a key adipokine in the metabolic syndrome. Diabetes Obes Metab 2006;8:264-80
43. Chaudhary N, Pfluger PT. Metabolic benefits from Sirt1 and Sirt1 activators. Curr Opin Clin Nutr Metab Care 2009;12:431-7
44. Rodgers JT, Lerin C, Haas W, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113-18 (Pubitemid 40349395)
45. Spiegelman BM. Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found Symp 2007;287:60-3
46. Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000;20:1868-76 (Pubitemid 30100203)
47. Estall JL, Kahn M, Cooper MP, et al. Sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression. Diabetes 2009;58:1499-508
48. Lomb DJ, Laurent G, Haigis MC. Sirtuins regulate key aspects of lipid metabolism. Biochim Biophys Acta 2010;1804:1652-7
49. Killalea SM, Krum H. Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease. Am J Cardiovasc Drugs 2001;1:193-204
50. Ashrafian H, Horowitz JD, Frenneaux MP. Perhexiline. Cardiovasc Drug Rev 2007;25:76-97 (Pubitemid 46625291)
51. Deschamps D, DeBeco V, Fisch C, et al. Inhibition by perhexiline of oxidative phosphorylation and the beta-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions. Hepatology 1994;19:948-61
52. Fromenty B, Fisch C, Labbe G, et al. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 1990;255:1371-6
53. Lewis JH, Mullick F, Ishak KG, et al. Histopathologic analysis of suspected amiodarone hepatotoxicity. Hum Pathol 1990;21:59-67
54. Kennedy JA, Unger SA, Horowitz JD. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol 1996;52:273-80 (Pubitemid 26233756)
55. McCarthy TC, Pollak PT, Hanniman EA, Sinal CJ. Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation. J Pharmacol Exp Ther 2004;311:864-73 (Pubitemid 39612690)
56. Freneaux E, Labbe G, Letteron P, et al. Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: possible role in microvesicular steatosis induced by this antibiotic. Hepatology 1988;8:1056-62
57. Le Dinh T, Freneaux E, Labbe G, et al. Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 1988;247:745-50
58. Geneve J, Hayat-Bonan B, Labbe G, et al. Inhibition of mitochondrial beta-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug. J Pharmacol Exp Ther 1987;242:1133-7 (Pubitemid 17156563)
59. Fromenty B, Freneaux E, Labbe G, et al. Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice. Biochem Pharmacol 1989;38:3743-51 (Pubitemid 19284022)
60. Silva MF, Aires CC, Luis PB, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis 2008;31:205-16
61. Natarajan SK, Eapen CE, Pullimood AB, Balasubramanian KA. Oxidative stress in experimental liver microvesicular steatosis: role of mitochondria and peroxisomes. J Gastroenterol Hepatol 2006;21:1240-9 (Pubitemid 44034335)
62. Jolly RA, Ciurlionis R, Morfitt D, et al. Microvesicular steatosis induced by a short chain fatty acid: effects on mitochondrial function and correlation with gene expression. Toxicol Pathol 2004;32(Suppl 2):19-25 (Pubitemid 38993912)
63. Berson A, De Beco V, Letteron P, et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 1998;114:764-74 (Pubitemid 28160411)
64. Kleiner DE, Gaffey MJ, Sallie R, et al. Histopathologic changes associated with fialuridine hepatotoxicity. Mod Pathol 1997;10:192-9 (Pubitemid 27130467)
65. Lai Y, Tse CM, Unadkat JD. Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs. J Biol Chem 2004;279:4490-7 (Pubitemid 38199039)
66. Lee EW, Lai Y, Zhang H, Unadkat JD. Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine. J Biol Chem 2006;281:16700-6
67. Hussain MM, Bakillah A. New approaches to target microsomal triglyceride transfer protein. Curr Opin Lipidol 2008;19:572-8
68. Puljak L, Parameswara V, Dolovcak S, et al. Evidence for AMPK-dependent regulation of exocytosis of lipoproteins in a model liver cell line. Exp Cell Res 2008;314:2100-9
69. Letteron P, Sutton A, Mansouri A, et al. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 2003;38:133-40 (Pubitemid 36775804)
70. Deboyser D, Goethals F, Krack G, Roberfroid M. Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes. Toxicol Appl Pharmacol 1989;97:473-9 (Pubitemid 19094963)
71. Lopez-Parra M, Titos E, Horrillo R, et al. Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice. J Lipid Res 2008;49:2513-23
72. Horrillo R, Gonzalez-Periz A, Martinez-Clemente M, et al. 5-lipoxygenase activating protein signals adipose tissue inflammation and lipid dysfunction in experimental obesity. J Immunol 2010;184:3978-87
73. Sugimoto T, Yamashita S, Ishigami M, et al. Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats. J Hepatol 2002;36:157-62 (Pubitemid 34146421)
74. Nossen JO, Rustan AC, Drevon CA. Calcium-antagonists inhibit secretion of very-low-density lipoprotein from cultured rat hepatocytes. Biochem J 1987;247:433-9 (Pubitemid 17153348)
75. Pan X, Hussain FN, Iqbal J, et al. Inhibiting proteasomal degradation of microsomal triglyceride transfer protein prevents CCl4-induced steatosis. J Biol Chem 2007;282:17078-89 (Pubitemid 47093224)
76. Boll M, Weber LW, Becker E, Stampfl A. Hepatocyte damage induced by carbon tetrachloride: inhibited lipoprotein secretion and changed lipoprotein composition. Z Naturforsch C 2001;56:283-90 (Pubitemid 32430530)
77. Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2003;33:105-36 (Pubitemid 36432872)
78. Larosche I, Letteron P, Fromenty B, et al. Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. J Pharmacol Exp Ther 2007;321:526-35 (Pubitemid 46624526)
79. Luiken JJ, Bonen A, Glatz JF. Cellular fatty acid uptake is acutely regulated by membrane-associated fatty acid-binding proteins. Prostaglandins Leukot Essent Fatty Acids 2002;67:73-8
80. Stremmel W, Pohl L, Ring A, Herrmann T. A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids. Lipids 2001;36:981-9 (Pubitemid 33065200)
81. van Oort MM, van Doorn JM, Hasnaoui ME, et al. Effects of AMPK activators on the sub-cellular distribution of fatty acid transporters CD36 and FABPpm. Arch Physiol Biochem 2009;115:137-46
82. Zhou J, Febbraio M, Wada T, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008;134:556-67
83. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115:1343-51 (Pubitemid 40629054)
84. Zhu L, Baker SS, Liu W, et al. Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. Metabolism 2010: published online 15 November 2010, DOI: 10.1016/j.metabol.2010. 10.003
85. Greco D, Kotronen A, Westerbacka J, et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008;294:G1281-7
86. Mattson MP, LaFerla FM, Chan SL, et al. Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2000;23:222-9 (Pubitemid 30236182)
87. Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 2005;115:2656-64 (Pubitemid 41434389)
88. Rao RV, Castro-Obregon S, Frankowski H, et al. Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. J Biol Chem 2002;277:21836-42 (Pubitemid 34952336)
89. Flamment M, Kammoun HL, Hainault I, et al. Endoplasmic reticulum stress: a new actor in the development of hepatic steatosis. Curr Opin Lipidol 2010;21:239-46
90. Ota T, Gayet C, Ginsberg HN. Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 2008;118:316-32
91. Kammoun HL, Hainault I, Ferre P, Foufelle F. Nutritional related liver disease: targeting the endoplasmic reticulum stress. Curr Opin Clin Nutr Metab Care 2009;12:575-82
92. Rahman SM, Qadri I, Janssen RC, Friedman JE. Fenofibrate and PBA prevent fatty acid-induced loss of adiponectin receptor and pAMPK in human hepatoma cells and in hepatitis C virus-induced steatosis. J Lipid Res 2009;50:2193-202
93. Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol 2010: published online 09 December 2010, DOI: 10.1016/j.jhep.2010.11.005
94. Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008;320:1492-6 (Pubitemid 351929428)
95. Glimcher LH, Lee AH. From sugar to fat: How the transcription factor XBP1 regulates hepatic lipogenesis. Ann NY Acad Sci 2009;1173(Suppl 1):E2-9
96. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett 2007;581:3641-51 (Pubitemid 47082516)
97. Lee AH, Glimcher LH. Intersection of the unfolded protein response and hepatic lipid metabolism. Cell Mol Life Sci 2009;66:2835-50
98. Schroeder-Gloeckler JM, Rahman SM, Janssen RC, et al. CCAAT/enhancerbinding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. J Biol Chem 2007;282:15717-29 (Pubitemid 47093283)
99. Pfaffenbach KT, Nivala AM, Reese L, et al. Rapamycin inhibits postprandial-mediated X-box-binding protein-1 splicing in rat liver. J Nutr 2010;140:879-84
100. Rutkowski DT, Wu J, Back SH, et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev Cell 2008;15:829-40
101. Sugden MC, Caton PW, Holness MJ. PPAR control: it?s SIRTainly as easy as PGC. J Endocrinol 2010;204:93-104
102. Moya M, Gomez-Lechon MJ, Castell JV, Jover R. Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. Chem Biol Interact 2010;184:376-87
103. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab 2009;20:72-7
104. Wolf G. Endogenous ligand for an orphan receptor. Nutr Rev 2010;68:316-18
105. Gao J, He J, Zhai Y, et al. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 2009;284:25984-92
106. Oosterveer MH, Grefhorst A, Groen AK, Kuipers F. The liver X receptor: control of cellular lipid homeostasis and beyond Implications for drug design. Prog Lipid Res 2010;49:343-52
107. Ide T, Shimano H, Yoshikawa T, et al. Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol 2003;17:1255-67 (Pubitemid 36819949)
108. Cha JY, Repa JJ. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem 2007;282:743-51 (Pubitemid 47076632)
109. Wojcicka G, Jamroz-Wisniewska A, Horoszewicz K, Be?towski J. Liver X receptors (LXRs). Part I: structure, function, regulation of activity, and role in lipid metabolism. Postepy Hig Med Dosw (Online) 2007;61:736-59
110. Peng D, Hiipakka RA, Xie JT, et al. A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR-/- mice. Br J Pharmacol 2011; Accepted Article; doi: 10.1111/j.1476- 5381.2011.01202.x
111. Grefhorst A, Elzinga BM, Voshol PJ, 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 2002;277:34182-90
112. Mitro N, Vargas L, Romeo R, et al. T0901317 is a potent PXR ligand: implications for the biology ascribed to LXR. FEBS Lett 2007;58:1721-6 (Pubitemid 46602262)
113. Wierzbicki M, Chabowski A, Zendzian-Piotrowska M, Gorski J. Differential effects of in vivo PPAR alpha and gamma activation on fatty acid transport proteins expression and lipid content in rat liver. J Physiol Pharmacol 2009;60:99-106
114. Kawano Y, Nishiumi S, Tanaka S, et al. Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport. Arch Biochem Biophys 2010;504:221-7
115. Huang J, Iqbal J, Saha PK, et al. Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 2007;46:147-57 (Pubitemid 47171931)
116. Lee JH, Zhou J, Xie W. PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks. Mol Pharm 2008;5:60-6 (Pubitemid 351300035)
117. Yin HQ, Kim M, Kim JH, et al. Hepatic gene expression profiling and lipid homeostasis in mice exposed to steatogenic drug, tetracycline. Toxicol Sci 2006;94:206-16 (Pubitemid 44542343)
118. Lee MH, Hong I, Kim M, et al. Gene expression profiles of murine fatty liver induced by the administration of methotrexate. Toxicology 2008;249:75-84
119. Lee MH, Hong I, Kim M, et al. Gene expression profiles of murine fatty liver induced by the administration of valproic acid. Toxicol Appl Pharmacol 2007;220:45-59 (Pubitemid 46427862)
120. Lelliott CJ, Lopez M, Curtis RK, et al. Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. FASEB J 2005;19:1108-19 (Pubitemid 40946436)
121. Amacher DE. Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies. Toxicology 2011;279:10-18
122. Amacher DE, Martin BA. Tetracycline-induced steatosis in primary canine hepatocyte cultures. Fundam Appl Toxicol 1997;40:256-63
123. McMillian MK, Grant ER, Zhong Z, et al. Nile Red binding to HepG2 cells: an improved assay for in vitro studies of hepatosteatosis. In Vitr Mol Toxicol 2001;14:177-90 (Pubitemid 34326670)
124. Donato MT, Martinez-Romero A, Jimenez N, et al. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem Biol Interact 2009;181:417-23
125. Fujimura H, Murakami N, Kurabe M, Toriumi W. In vitro assay for drug-induced hepatosteatosis using rat primary hepatocytes, a fluorescent lipid analog and gene expression analysis. J Appl Toxicol 2009;29:356-63
126. Pessayre D, Larrey D. Acute and chronic drug-induced hepatitis. Baillieres Clin Gastroenterol 1988;2:385-422
127. Viollet B, Athea Y, Mounier R, et al. AMPK: Lessons from transgenic and knockout animals. Front Biosci 2009;14:19-44
128. Akkaoui M, Cohen I, Esnous C, et al. Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids. Biochem J 2009;420:429-38
129. Kerner J, Hoppel C. Fatty acid import into mitochondria. Biochim Biophys Acta 2000;1486(1):17
130. Baur JA. Biochemical effects of SIRT1 activators. Biochim Biophys Acta 2010;1804:1626-34
131. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125-31 (Pubitemid 34496588)
132. Krycer JR, Sharpe LJ, Luu W, Brown AJ. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 2010;21:268-76
133. Eberle D, Hegarty B, Bossard P, et al. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 2004;86:839-48 (Pubitemid 39602764)