Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice.
In order to investigate the role of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) in the pathogenesis of hepatic steatosis and hepatic insulin resistance, we examined whole-body insulin action in awake mtGPAT1 knockout (mtGPAT1(-/-)) and wild-type (wt) mice after regular control diet or three weeks of high-fat feeding. In contrast to high-fat-fed wt mice, mtGPAT1(-/-) mice displayed markedly lower hepatic triacylglycerol and diacylglycerol concentrations and were protected from hepatic insulin resistance possibly due to a lower diacylglycerol-mediated PKC activation. Hepatic acyl-CoA has previously been implicated in the pathogenesis of insulin resistance. Surprisingly, compared to wt mice, mtGPAT1(-/-) mice exhibited increased hepatic insulin sensitivity despite an almost 2-fold elevation in hepatic acyl-CoA content. These data suggest that mtGPAT1 might serve as a novel target for treatment of hepatic steatosis and hepatic insulin resistance and that long chain acyl-CoA's do not mediate fat-induced hepatic insulin resistance in this model.
Neschen
Susanne
S
Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven, CN 06520, USA.
Morino
Katsutaro
K
Hammond
Linda E
LE
Zhang
Dongyan
D
Liu
Zhen-Xiang
ZX
Romanelli
Anthony J
AJ
Cline
Gary W
GW
Pongratz
Rebecca L
RL
Zhang
Xian-Man
XM
Choi
Cheol S
CS
Coleman
Rosalind A
RA
Shulman
Gerald I
GI
D055372:AMP-Activated Protein Kinases; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism; D005215:Fasting; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D005951:Glucose Tolerance Test; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D004075:Diglycerides; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D005992:Glycerol-3-Phosphate O-Acyltransferase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase