Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease.
Short term high fat feeding in rats results specifically in hepatic fat accumulation and provides a model of non-alcoholic fatty liver disease in which to study the mechanism of hepatic insulin resistance. Short term fat feeding (FF) caused a approximately 3-fold increase in liver triglyceride and total fatty acyl-CoA content without any significant increase in visceral or skeletal muscle fat content. Suppression of endogenous glucose production (EGP) by insulin was diminished in the FF group, despite normal basal EGP and insulin-stimulated peripheral glucose disposal. Hepatic insulin resistance could be attributed to impaired insulin-stimulated IRS-1 and IRS-2 tyrosine phosphorylation. These changes were associated with activation of PKC-epsilon and JNK1. Ultimately, hepatic fat accumulation decreased insulin activation of glycogen synthase and increased gluconeogenesis. Treatment of the FF group with low dose 2,4-dinitrophenol to increase energy expenditure abrogated the development of fatty liver, hepatic insulin resistance, activation of PKC-epsilon and JNK1, and defects in insulin signaling. In conclusion, these data support the hypothesis hepatic steatosis leads to hepatic insulin resistance by stimulating gluconeogenesis and activating PKC-epsilon and JNK1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase.
Samuel
Varman T
VT
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Liu
Zhen-Xiang
ZX
Qu
Xianqin
X
Elder
Benjamin D
BD
Bilz
Stefan
S
Befroy
Douglas
D
Romanelli
Anthony J
AJ
Shulman
Gerald I
GI
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D005227:Fatty Acids; D007328:Insulin; D020033:Protein Isoforms; D012333:RNA, Messenger; D014443:Tyrosine; D006003:Glycogen; D003847:Deoxyglucose; D006006:Glycogen Synthase; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases