The role of hepatic lipid accumulation in the development of insulin resistance in the liver;Akumulacja lipidów (triacylo-, diacylogliceroli i ceramidów) wewna̧trz hepatocytów, a rozwój insulinooporności wa̧trobowej

Postepy Higieny i Medycyny Doswiadczalnej

Volumn 65, Issue , 2011, Pages 236-243

  Konstantynowicz, Karolina ^a   Mikłosz, Agnieszka ^a   Stepek, Tomasz ^a   Chabowski, Adrian ^a  

^a Zak ad Fizjologii   (Poland)

Author keywords

Ceramides; Diacylglycerols; Hepatocytes; Insulin resistance; Triacylglycerols

Indexed keywords

EID: 79958841022     PISSN: 00325449     EISSN: 17322693     Source Type: Journal    
DOI: 10.5604/17322693.939285     Document Type: Review

References (96)

1. Alessi D.R., Downes C.P.: The role of PI3K in insulin action. Biochim. Biophys. Acta, 1998; 1436: 151-164.
2. nd International Congress on "Prediabetes" and the metabolic syndrome. Barcelona, April 2007; 25-28.
3. Anthony K., Bingham E., Dunn J., Reed L., Marsden P., Amiel S.A.: Altered brain glucose uptake in insulin resistance syndrome: a mechanism for cognitive impairment and abnormal feeding behaviour? 1st International Congress on "Prediabetes" and the metabolic syndrome. Berlin, April 2005; 13-16.
4. Antonetti D.A., Algenstaedt P., Kahn C.R.: Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol. Cell. Biol., 1996; 16: 2195-2203. (Pubitemid 26123740)
5. Barazzoni R., Kiwanuka E., Zanetti M., Cristini M., Vettore M., Tessari P.: Insulin acutely increases fibrinogen production in individuals with type 2 diabetes but not in individuals without diabetes. Diabetes, 2003; 52: 1851-1856. (Pubitemid 36792478)
6. Barter P.: The realities of dyslipidaemia in metabolic syndrome and diabetes. Br. J. Diabetes Vasc. Dis., 2005; 5(Suppl.1): S7-S11. (Pubitemid 41320540)
7. Belfort R., Harrison S.A., Brown K., Darland C., Finch J., Hardies J., Balas B., Gastaldelli A., Tio F., Pulcini J., Berria R., Ma J.Z., Dwivedi S., Havranek R., Fincke C., DeFronzo R., Bannayan G.A., Schenker S., Cusi K.: A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med., 2006; 355: 2297-2307. (Pubitemid 44837778)
8. Carrasco S., Merida I.: Diacylglycerol, when simplicity becomes complex. Trends Biochem. Sci., 2007; 32: 27-36. (Pubitemid 46038735)
9. Chang L., Chiang S.H., Saltiel A.R.: Insulin signaling and the regulation of glucose transport. Mol. Med., 2004; 10: 65-71. (Pubitemid 41825486)
10. Chavez J.A., Knotts T.A., Wang L.P, Li G., Dobrowsky R.T., Florant G.L., Summers S.A.: A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. J. Biol. Chem., 2003; 278: 10297-10303. (Pubitemid 36800291)
11. Chen M.T., Kaufman L.N., Spennetta T., Shrago E.: Effects of high fatfeeding to rats on the interrelationship of body weight, plasma insulin, and fatty acyl-coenzyme A esters in liver and skeletal muscle. Metabolism, 1992; 41: 564-569.
12. Chin J.E., Dickens M., Tavare J.M., Roth R.A.: Overexpression of protein kinase C isoenzymes a, bI, g, and e in cells overexpressing the insulin receptor. Effects on receptor phosphorylation and signaling. J. Biol. Chem., 1993; 268: 6338-6347. (Pubitemid 23099328)
13. Czyzyk A.: Patofizjologia i klinika cukrzycy. Wydawnictwo Naukowe PWN, Warszawa 1997.
14. Day C.P.: Pathogenesis of steatohepatitis. Best. Pract. Res. Clin. Gastroenterol., 2002; 16: 663-678.
15. De Fea K., Roth R.A.: Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry, 1997; 36: 12939-12947. (Pubitemid 27465406)
16. Diraison F., Moulin P., 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., 2003; 29: 478-485. (Pubitemid 37474259)
17. Donnelly K.L., Smith C.I., Schwarzenberg S.J., Jessurun J., Boldt M.D., Parks E.J.: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest., 2005; 115: 1343-1351. (Pubitemid 40629054)
18. Duguay L., Coutu D., Hetu C., Joly J.G.: Inhibition of liver regeneration by chronic alcohol administration. Gut, 1982; 23: 8-13. (Pubitemid 12170169)
19. Eckel R.H., Grundy S.M., Zimmet P.Z.: The metabolic syndrome. Lancet, 2005; 365: 1415-1428. (Pubitemid 40523737)
20. Etgan G.J., Valasek K.M., Broderick C.L.: In vivo adenoviral delivery of recombinant human protein kinase C-ζ stimulates glucose transport activity in rat skeletal muscle. J. Biol. Chem., 1999; 274: 22139-22142.
21. Gastaldelli A., Harrison S.A., Belfort-Aguilar R., Hardies L.J., Balas B., Schenker S., Cusi K.: Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology, 2009; 50: 1087-1093.
22. Gibbons G.F., Brown A.M., Wiggins D., Pease R.: The roles of insulin and fatty acids in the regulation of hepatic very-low-density lipoprotein assembly. J. R. Soc. Med., 2002; 95, Suppl. 42: 29-32.
23. Giddings S.J., Carnaghi L.R.: Insulin receptor gene expression during development: developmental regulation of insulin receptor mRNA abundance in embryonic rat liver and yolk sac, developmental regulation of insulin gene splicing, and comparison to abundance of insulin-like growth factor 1 receptor mRNA. Mol. Endocrinol., 1992; 6: 1665-1672.
24. Ginsberg H.N.: Efficiacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia. J. Clin. Endocrinol. Metab., 2006; 91: 383-392. (Pubitemid 43236897)
25. Govers R., Coster A.C., James D.E.: Insulin increases cell surface GLUT4 levels by dose dependently discharging GLUT4 into a cell surface recycling pathway. Mol. Cell Biol., 2004; 24: 6456-6466. (Pubitemid 38891144)
26. Greenberg A.S., Nordan R.P., Mclntosh J., Calvo J.C., Scow R.O., Jablons D.: Interleukin-6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia. Cancer Res., 1992; 52: 4113-4116.
27. Griffin M.E., Marcucci M.J., Cline G.W., Bell K., Barucci N., Lee D., Goodyear L.J., Kraegen E.W., White M.F., Shulman G.I.: Free fatty acid-induced insulin resistance is associated with activation of pro-tein kinase Cζ and alterations in the insulin cascade. Diabetes, 1999; 48: 1270-1274. (Pubitemid 29241025)
28. Grundy S.M., Brewer H.B.Jr, Cleeman J.I., Smith S.C.Jr, Lenfant C.: Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to definition. Circulation, 2004; 109: 433-438.
29. Hassan M.M., Hwang L.Y., Hatten C.J., Swaim M., Li D., Abbruzzese J.L., Beasley P., Patt Y.Z.: Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology, 2002; 36: 1206-1213. (Pubitemid 35253437)
30. Hellemans K., Kerckhofs K., Hannaert J.C., Martens G., Van Veldhoven P., Pipeleers D.: Peroxisome proliferator-activated receptor alpha-retinoid X receptor agonists induce beta-cell protection against palmitate toxicity. FEBS J., 2007; 274: 6094-6105. (Pubitemid 350135331)
31. Hellerstein M.K., Neese R.A., Schwarz J.M., Turner S., Faix D., Wu K.: Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats. Am. J. Physiol., 1997; 272: E163-E172.
32. Holland W.L., Knotts T.A., Chavez J.A., Wang L.P., Hoehn K.L., Summers S.A.: Lipid mediators of insulin resistance. Nutr. Rev., 2007; 65: S39-S46.
33. Holland W.L., Summers S.A.: Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev., 2008; 29: 381-402. (Pubitemid 351831506)
34. Hotamisligil G.S., Peraldi P., Budavari A., Ellis R., White M.F., Spiegelman B.M.: IRS-1 mediated inhibition of insulin receptor tyrosine kinase activity in TNF-a and obesity-induced insulin resistance. Science, 1996; 271: 665-668. (Pubitemid 26052915)
35. Hue L., Maisin L., Rider M.H.: Palmitate inhibits liver glycolisis; involment of fructose 2, 6-biophosphatase in the glucose/fatty acid cycle. Bioch. J., 1988; 251: 541-545.
36. Jelski W., Chrostek L., Szmitkowski M.: Biochemiczne podstawy alkoholowego uszkodzenia w a̧troby. Pol. Merk. Lek., 2006; 124: 376-380. (Pubitemid 44759461)
37. Juhan-Vague I., Alessi M.C., Mavri A., Morange P.E.: Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J. Thromb. Haemost., 2003; 1: 1575-1579.
38. Kanety H., Feinstein R., Papa M.Z., Hemi R., Karasik A.: Tumor necrosis factor a-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J. Biol. Chem., 1995; 270: 23780-23784.
39. Kawaguchi T., Yoshida T., Harada M., Hisamoto T., Nagao Y., Ide T., Taniguchi E., Kumemura H., Hanada S., Maeyama M., Baba S., Koga H., Kumashiro R., Ueno T., Ogata H., Yoshimura A., Sata M.: Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am. J. Pathol., 2004; 165: 1499-1508. (Pubitemid 39435150)
40. Kim J.K., Fillmore J.J., Chen Y., Yu C., Moore I.K., Pypaert M., Lutz E.P., Kako Y., Velez-Carrasco W., Goldberg I.J., Breslow J.L., Shulman G.I.: Tissue-specific overexpression of lipoprotein lipase causes tisue-specific insulin resistance. Proc. Natl. Acad. Sci. USA, 2001; 98: 7522-7527. (Pubitemid 32567981)
41. Klip A., Paquet M.R.: Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care, 1990; 13: 228-243. (Pubitemid 20092110)
42. Kohler H.P. Grant P.J.: Plasminogen activator inhibitor type 1 and coronary artery disease. N. Engl. J. Med., 2000; 342: 1792-1801. (Pubitemid 30390240)
43. Krook A., Bjornholm M., Galuska D., Jiang X.J., Fahlman R., Myers M.G.Jr., Wallberg-Henriksson H., Zierath J.R.: Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes, 2000; 49: 284-292. (Pubitemid 30071007)
44. Kuper H., Tzonou A., Kaklamani E., Hsieh C.C., Lagiou P., Adami H.O., Trichopoulos D., Stuver S.O.: Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. Int. J. Cancer, 2000; 85: 498-502. (Pubitemid 30075127)
45. Lam T.K., Yoshii H., Haber C.A., Bogdanovic E., Lam L., Fantus I.G., Giacca A.: Free fatty acid induced hepatic insulin resistance: a potential role protein kinase C-δ. Am. J. Physiol. Endocrinol. Metab., 2002; 283: E682-E691.
46. Le Roith D., Zick Y.: Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care, 2001; 24: 588-597. (Pubitemid 32198431)
47. Lee J., Pilch P.F., Shoelson S.E., Scarlata S.F.: Conformational changes of the IR upon insulin binding and activation as monitored fluorescence spectroscopy. Biochemisty, 1997; 36: 2701-2708. (Pubitemid 27106665)
48. Li X.L., Man K., Ng K.T., Sun C.K., Lo C.M., Fan S.T.: The influence of phosphatidylinositol 3-kinase/Akt pathway on the ischemic injury during rat liver graft preservation. Am. J. Transplant., 2005; 5: 1264-1275. (Pubitemid 40839414)
49. Lieber C.S.: Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol, 2004; 34: 9-19. (Pubitemid 40163989)
50. Loskutoff D.J., Samad F.: The adipocyte and hemostatic balance in obesity. Studies of PAI-1. Arterioscler. Thromb. Vasc. Biol., 1998; 18: 1-6. (Pubitemid 28047591)
51. Machado M., Cortez-Pinto H.: Non-alcoholic fatty liver disease and insulin resistance. Eur. J. Gastroenterol. Hepatol., 2005; 17: 823-826. (Pubitemid 41073319)
52. Magnusson I., Rothman D.L., Katz L.D., Shulman G.I.: Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest., 1992; 90: 1323-1327.
53. Marchesini G., Brizi M., Bianchi G., Tomassetti S., Bugianesi E., Lenzi M., McCullough A.J., Forlani G., Natale S., Melchionda N.: Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes, 2001; 50: 1844-1850. (Pubitemid 33641605)
54. Marchesini G., Brizi M., Morselli-Labate A.M., Bianchi G., Bugianesi E., McCullough A.J., Forlani G., Melchionda N.: Association on nonalcoholic fatty liver disease with insulin resistance. Am. J. Med., 1999; 107: 450-455. (Pubitemid 29528333)
55. Mason A.L., Lau J.Y., Hoang N., Qian K., Alexander G.J., Xu L., Guo L., Jacob S., Regenstein F.G., Zimmerman R., Everhart J.E., Wasserfall C., Maclaren N.K., Perrillo R.P.: Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology, 1999; 29: 328-333. (Pubitemid 29088433)
56. McAuley K.A., Williams S.M., Mann J.I., Walker R.J., Lewis-Barned N.J., Temple L.A., Duncan A.W.: Diagnosing insulin resistance in the general population. Diabetes Care, 2001; 24: 460-464. (Pubitemid 32198413)
57. McVicker B.L., Tuma D.J., Kubik J.L., Tuma P.L., Casey C.A.: Ethanol-induced apoptosis in polarized hepatic cells possibly through regulation of the Fas pathway. Alcohol. Clin. Exp. Res., 2006; 30: 1906-1915. (Pubitemid 44630094)
58. Mertens I., Van Gaal L.F.: Obesity, haemostasis and the fibrinolytic system. Obes. Rev., 2002; 3: 85-101. (Pubitemid 34827150)
59. Meyer S.G., de Groot H.: Cycloserine and threo-dihydrosphingosine inhibit TNF-a-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-a signaling. Biochim. Biophys. Acta, 2003; 1643: 1-4. (Pubitemid 37494886)
60. Monetti M., Levin M.C., Watt M.J., Sajan M.P., Marmor S., Hubbard B.K., Stevens R.D., Bain J.R., Newgard C.B., Farese R.V. Sr, Hevener A.L., Farese R.V. Jr.: Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab., 2007; 6: 69-78. (Pubitemid 46995777)
61. Napoli J., Bishop G.A., McGuinness P.H., Painter D.M., McCaughan G.W.: Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology, 1996; 24: 759-765. (Pubitemid 26334270)
62. Neuschwander-Tetri B.A., Caldwell S.H.: Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology, 2003; 37: 1202-1219. (Pubitemid 36538699)
63. Nonogaki K., Fuller G.M., Fuentes N.L., Moser A.H., Staprans I., Grunfeld C., Feingold K.R.: Interleukin-6 stimulates hepatic trigliceride secretion in rats. Endocrinology, 1995; 136: 2143-2148.
64. Oakes N.D., Cooney G.J., Camilleri S., Chisholm D.J., Kraegen E.W.: Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding. Diabetes, 1997; 46: 1768-1774. (Pubitemid 27456409)
65. Olszanecka-Glinianowicz M., Zahorska-Markiewicz B., Kocełak P., Janowska J., Holecki M., Semik-Grabarczyk E.: Wpływ redukcji masy ciała na stȩżenie interleukiny-6 (IL-6) i insulinooporność. Endokrynol. Pol., 2006; 57: 131-135.
66. Onishi Y, Honda M., Ogihara T., Sakoda H., Anai M., Fujishiro M., Ono H., Shojima N., Fukushima Y., Inukai K., Katagiri H., Kikuchi M., Oka Y., Asano T.: Ethanol feeding induces insulin resistance with enhanced PI 3-kinase activation. Biochem. Biophys. Res. Commun., 2003; 303: 788-794. (Pubitemid 36384924)
67. Orellana A., Hidalgo P.C., Morales M.N., Mezzano D., Bronfman M.: Palmitoyl-CoA and the acyl-CoA thioester of the carcinogenic peroxisome- proliferator ciprofibrate potentiate diacylglycerol-activated protein kinase C by decreasing the phosphatidylserine requirement of the enzyme. Eur. J. Biochem., 1990; 190: 57-61. (Pubitemid 20183964)
68. Otani K., Korenaga M., Beard M.R., Li K., Qian T., Showalter L.A., Singh A.K., Wang T., Weinman S.A.: Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology, 2005; 128: 96-107. (Pubitemid 40039962)
69. Patel B.C., D'Arville C., Iwahashi M., Simon F.R.: Impairment of hepatic insulin receptors during chronic ethanol administration. Am. J. Physiol., 1991; 261: G199-G205.
70. Patti M.E., Kahn C.R.: The insulin receptor-a critical link in glucose homeostasis and insulin action. J. Basic. Clin. Physiol. Pharmacol., 1998; 9: 89-109. (Pubitemid 29143595)
71. Paz K., Hemi R., Le Roith D., Karasik A., Elhanany E., Kanety H., Zick Y.: A molecular basis for insulin resistance: elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J. Biol. Chem., 1997; 272: 29911-29918.
72. Pettus B.J., Chalfant C.E., Hannun Y.A.: Sphingolipids in inflammation: roles and implications. Curr. Mol. Med., 2004; 4: 405-418. (Pubitemid 38787009)
73. Puri P., Mirshahi F., Cheung O., Natarajan R., Maher J.W., Kellum J.M., Sanyal A.J.: Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology, 2008; 134: 568-576. (Pubitemid 351173040)
74. Raynaud E., Perez-Martin A., Brun J., Aissa-Benhaddad A., Fedou C., Mercier J.: Relationships between fibrinogen and insulin resistance. Atherosclerosis, 2000; 150: 365-370. (Pubitemid 30336548)
75. Ricchi M., Odoardi M.R., Carulli L., Anzivino C., Ballestri S., Pinetti A., Fantoni L.I., Marra F., Bertolotti M., Banni S., Lonardo A., Carulli N., Loria P.: Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J. Gastroenterol. Hepatol., 2009; 24: 830-840.
76. Rigamonti C., Mottaran E., Reale E., Rolla R., Cipriani V., Capelli F., Boldorini R., Vidali M., Sartori M., Albano E.: Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology, 2003; 38: 42-49. (Pubitemid 36775794)
77. Rothman D.L., Magnusson I., Katz L.D., Shulman R.G., Shulman G.I.: Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science, 1991; 254: 573-576. (Pubitemid 21917377)
78. Rutter G.A.: Diabetes: The importance of the liver. Curr. Biol., 2000; 10: R736-R738.
79. Sasaki Y., Wands J.R.: Ethanol impairs insulin receptor substrate-1 mediated signal transduction during rat liver regeneration. Biochem. Biophys. Res. Commun., 1994; 199: 403-409.
80. Seeff L.B.: Natural history of chronic hepatitis C. Hepatology, 2002; 36: S35-S46. (Pubitemid 35253462)
81. Seifert R., Schachtele C., Rosenthal W., Schultz G.: Activation of protein kinase C by cis- and trans-fatty acids and its potentiation by diacylglycerol. Biochem. Biophys. Res. Commun., 1988; 154: 20-26.
82. Skolnik E.Y., Batzer A., Li N., Lee C.H., Lowenstein E., Mohammadi M., Margolis B., Schlessinger J.: The function of GRB2 in linking the insulin receptor to ras signalling pathways. Science, 1993; 260: 1953-1955. (Pubitemid 23258278)
83. Summers S.A.: Ceramides in insulin resistance and lipotoxicity. Prog. Lipid Res., 2006; 45: 42-72. (Pubitemid 43170804)
84. Taniguchi C.M., Kondo T., Sajan M., Luo J., Bronson R., Asano T., Farese R., Cantley L.C., Kahn C.R.: Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKC-lambda/zeta. Cell Metab., 2006; 3: 343-353.
85. Tappy L., Minehira K.: New data and new concepts on the role of the liver in glucose homeostasis. Curr. Opin. Clin. Nutr. Metab. Care, 2001; 4: 273-277. (Pubitemid 34755440)
86. Teruel T., Hernandez R., Lorenzo M.: Ceramide mediates insulin resistance by TNF-a in brown adipocytes by maintaining Akt in an inactive dephosphorylated state. Diabetes, 2001; 50: 2563-2571. (Pubitemid 33642775)
87. Thomas E.L., Hamilton G., Patel N., O'Dwyer R., Doré C.J., Goldin R.D., Bell J.D., Taylor-Robinson S.D.: Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. Gut, 2005; 54: 122-127. (Pubitemid 40007230)
88. Unger R.H.: Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol. Metab., 2003; 14: 398-403. (Pubitemid 37392211)
89. Unger R.H.: Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology, 2003; 144: 5159-5165. (Pubitemid 37476041)
90. Unger R.H.: The physiology of cellular liporegulation. Annu. Rev. Physiol., 2003; 65: 333-347. (Pubitemid 38249157)
91. Virkamaki A., Ueki K., Kahn C.R.: Protein-protein interaction in insulin signalling and the molecular mechanism of insulin resistance. J. Clin. Invest., 1999; 103: 931-943. (Pubitemid 29169600)
92. Wanless I.R., Shiota K.: The pathogenesis of nonalcoholic steatohepatitis and other fatty liver disease: a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis. Semin. Liver Dis., 2004; 24: 99-106. (Pubitemid 38496052)
93. White M.F., Kahn C.R.: The insulin-signaling system. J. Biol. Chem., 1994; 269: 1-4.
94. Wieckowska A., Papouchado B.G., Li Z., Lopez R., Zein N.N., Feldstein A.E.: Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol., 2008; 103: 1372-1379. (Pubitemid 351813900)
95. Wierzbicki M., Chabowski A., Zendzian-Piotrowska M., Harasim E., Górski J.: Chronic, in vivo, PPARalpha activation prevents lipid overload in rat liver induced by high fat feeding. Adv. Med. Sci., 2009; 54: 59-65.
96. Yeon J.E., Califano S., Xu J., Wands J.R., De La Monte S.M.: Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver. Hepatology, 2003; 38: 703-714. (Pubitemid 37052157)