Insights into the pathogenesis of NAFLD: The role of metabolic and pro-inflammatory mediators

Annals of Gastroenterology

Volumn 22, Issue 1, 2009, Pages 24-33

  Xirouchakis, Elisa ^a   Manousou, Penelopi ^b   Tsartsali, Lemonia ^c   Georgopoulos, S ^a   Burroughs, A K ^b  

^a Athens Medical   (Greece)

^b ROYAL FREE HOSPITAL   (United Kingdom)

^c AGHIA SOPHIA CHILDREN S HOSPITAL   (Greece)

Author keywords

Adiponectin; Cytokines; Insulin receptor; Leptin receptor; Non alcoholic fatty liver disease

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; ADENYLATE KINASE; ADIPONECTIN; ADVANCED GLYCATION END PRODUCT; CARNITINE PALMITOYLTRANSFERASE I; FATTY ACID; GLUCOSE TRANSPORTER 4; GLYCEROL 3 PHOSPHATE ACYLTRANSFERASE; I KAPPA B KINASE BETA; INSULIN; INSULIN RECEPTOR; INTERLEUKIN 1BETA; INTERLEUKIN 6; LEPTIN; LONG CHAIN FATTY ACID COENZYME A LIGASE; MITOGEN ACTIVATED PROTEIN KINASE KINASE 4; NEUROPEPTIDE Y; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; STEROL REGULATORY ELEMENT BINDING PROTEIN 1C; SUPPRESSOR OF CYTOKINE SIGNALING 3; TUMOR NECROSIS FACTOR ALPHA; UNCOUPLING PROTEIN 2; VERY LOW DENSITY LIPOPROTEIN;

CYTOKINE RELEASE; ENZYME ACTIVATION; ENZYME ACTIVITY; FATTY ACID OXIDATION; GLUCOSE INTOLERANCE; GLYCATION; HUMAN; HYPERGLYCEMIA; INFLAMMATION; INSULIN RESISTANCE; LIPID STORAGE; LIPOGENESIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REVIEW; SIGNAL TRANSDUCTION;

EID: 67651089476     PISSN: 11087471     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (85)

1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346:1221-1231.
2. Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 2008; 28339-350.
3. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004; 24:3-20.
4. Day CP. From fat to inflammation. Gastroenterology 2006; 130:207-210.
5. Xirouchakis E, Sigalas A, Manousou P, Calvaruso V, Pleguezuelo M, Corbani A et al. Models for non-alcoholic fatty liver disease: a link with vascular risk. Curr Pharm Des 2008; 14:378-384.
6. Unger RH. Lipotoxic diseases. Annu Rev Med 2002; 53:319-336.
7. Leclercq IA, da Silva MA, Schroyen B, Van HN, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J Hepatol 2007; 47:142-156.
8. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology 1998; 114:842-845.
9. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005; 42:987-1000.
10. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004; 89(6):2548-2556.
11. Hamilton JA. Fatty acid transport: difficult or easy? J Lipid Res 1998; 39:467-481.
12. Foufelle F, Ferre P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J 2002; 366(Pt 2):377-391.
13. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes 1991; 40:405-412.
14. Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 2005; 15:16R-28R.
15. Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 2006; 147:943-951.
16. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 2006; 291:E275-E281.
17. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001; 120:1183-1192.
18. Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002; 35:373-379.
19. Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology 2002; 35:367-372.
20. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414(6865):799-806.
21. Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995; 75:473-486.
22. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115:1111-1119.
23. Previs SF, Withers DJ, Ren JM, White MF, Shulman GI. Contrasting effects of IRS-1 versus IRS-2 gene disruption on carbohydrate and lipid metabolism in vivo. J Biol Chem 2000; 275:38990-38994.
24. Biddinger SB, Kahn CR. From mice to men: insights into the insulin resistance syndromes. Annu Rev Physiol 2006; 68:123-158.
25. Nandi A, Kitamura Y, Kahn CR, Accili D. Mouse models of insulin resistance. Physiol Rev 2004; 84:623-647.
26. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 2000; 6:87-97.
27. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998; 2:559-569.
28. Kim JK, Michael MD, Previs SF, Peroni OD, Mauvais-Jarvis F, Neschen S et al. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J Clin Invest 2000; 105:1791-1797.
29. Bluher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 2002; 3:25-38.
30. 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; 109:1125-1131.
31. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83:1263-1271.
32. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000; 68:437-446.
33. Ghilardi N, Ziegler S, Wiestner A, Stoffel R, Heim MH, Skoda RC. Defective STAT signaling by the leptin receptor in diabetic mice. Proc Natl Acad Sci U S A 1996; 93:6231-6235.
34. Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 62:413-437.
35. Dube MG, Xu B, Kalra PS, Sninsky CA, Kalra SP. Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats. Brain Res 1999; 816:38-46.
36. Williams G, Cardoso HM, Domin J, Ghatei MA, Russell JC, Bloom SR. Hypothalamic regulatory peptide disturbances in the spontaneously obese JCR: LA-corpulent rat. Diabetes Res 1990; 15:1-7.
37. Russell JC, Amy RM, Graham SE, Dolphin PJ, Wood GO, Bar-Tana J. Inhibition of atherosclerosis and myocardial lesions in the JCR:LA-cp rat by beta, beta'-tetramethylhexadecanedioic acid (MEDICA 16). Arterioscler Thromb Vasc Biol 1995; 15:918-923.
38. Surwit RS, Edwards CL, Murthy S, Petro AE. Transient effects of long-term leptin supplementation in the prevention of diet-induced obesity in mice. Diabetes 2000; 49:1203-1208.
39. Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV. Leptin: the tale of an obesity gene. Diabetes 1996; 45:1455-1462.
40. Shimabukuro M, Koyama K, Chen G, Wang MY, Trieu F, Lee Y et al. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A 1997; 94:4637-4641.
41. Wang MY, Koyama K, Shimabukuro M, Mangelsdorf D, Newgard CB, Unger RH. Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion. Proc Natl Acad Sci U S A 1998; 95:11921-11926.
42. Wang MY, Koyama K, Shimabukuro M, Newgard CB, Unger RH. OB-Rb gene transfer to leptin-resistant islets reverses diabetogenic phenotype. Proc Natl Acad Sci U S A 1998; 95:714-718.
43. Kakuma T, Lee Y, Higa M, Wang Z, Pan W, Shimomura I et al. Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci U S A 2000; 97:8536-8541.
44. Zhou YT, Shimabukuro M, Lee Y, Koyama K, Higa M, Ferguson T et al. Enhanced de novo lipogenesis in the leptinunresponsive pancreatic islets of prediabetic Zucker diabetic fatty rats: role in the pathogenesis of lipotoxic diabetes. Diabetes 1998; 47:1904-1908.
45. Lee Y, Hirose H, Zhou YT, Esser V, McGarry JD, Unger RH. Increased lipogenic capacity of the islets of obese rats: a role in the pathogenesis of NIDDM. Diabetes 1997; 46:408-413.
46. Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci U S A 1993; 90:2160-2164.
47. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A 1994; 91:7355-7359.
48. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996; 1302:93-109.
49. Zhou YT, Shimabukuro M, Wang MY, Lee Y, Higa M, Milburn JL et al. Role of peroxisome proliferator-activated receptor alpha in disease of pancreatic beta cells. Proc Natl Acad Sci U S A 1998; 95:8898-8903.
50. bu-Elheiga L, Matzuk MM, bo-Hashema KA, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 2001; 291:2613-2616.
51. McGarry JD, Mannaerts GP, Foster DW. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 1977; 60:265-270.
52. Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J 2000; 345 Pt 2:161-179.
53. Weiss B, Stoffel W. Human and murine serine-palmitoyl-CoA transferase-cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Eur J Biochem 1997; 249:239-247.
54. Shimabukuro M, Higa M, Zhou YT, Wang MY, Newgard CB, Unger RH. Lipoapoptosis in beta-cells of obese prediabetic fa/fa rats. Role of serine palmitoyltransferase overexpression. J Biol Chem 1998; 273:32487-32490.
55. Shimabukuro M, Wang MY, Zhou YT, Newgard CB, Unger RH. Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci U S A 1998; 95:9558-9561.
56. Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 2002; 122:1399-1410.
57. Ikejima K, Honda H, Yoshikawa M, Hirose M, Kitamura T, Takei Y et al. Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals. Hepatology 2001; 34:288-297.
58. Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001; 21:89-104.
59. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116:1784-1792.
60. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8:731-737.
61. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8:1288-1295.
62. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999; 103:1489-1498.
63. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 2000; 275:36703-36707.
64. Bugianesi E, Pagotto U, Manini R, Vanni E, Gastaldelli A, de IR et al. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab 2005; 90:3498-3504.
65. Maher JJ. Interactions between hepatic stellate cells and the immune system. Semin Liver Dis 2001; 21(3):417-426.
66. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115:209-218.
67. Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM et al. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. Diabetes 2002; 51:3176-3188.
68. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology 2004; 40:185-194.
69. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293:1673-1677.
70. Hirosumi J, Tuncman G, Chang LF, Gorgun CZ, Uysal KT, Maeda K et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420:333-336.
71. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 1997; 389:610-614.
72. Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396:77-80.
73. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293:1673-1677.
74. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001; 108:437-446.
75. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 2005; 11:183-190.
76. Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ et al. SOCS-3 inhibits insulin signaling and is upregulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 2001; 276:47944-47949.
77. Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 2003; 278:13740-13746.
78. Ueki K, Kondo T, Tseng YH, Kahn CR. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A 2004; 101:10422-10427.
79. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006; 7:85-96.
80. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 2003; 52:2784-2789.
81. Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology 2005; 146:3417-3427.
82. Lalor PF, Faint J, Aarbodem Y, Hubscher SG, Adams DH. The role of cytokines and chemokines in the development of steatohepatitis. Semin Liver Dis 2007; 27:173-193.
83. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116:1793-1801.
84. Calvert VS, Collantes R, Elarinv H, Afendy A, Baranova A, Mendoza M et al. A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis. Hepatology 2007; 46:166-172.
85. Ma KL, Ruan XZ, Powis SH, Chen Y, Moorhead JF, Varghese Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 2008; 48:770-781.