Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance.
Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial beta-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an approximately 40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50% decrease in Akt2 activation. These changes were associated with increased PKCepsilon activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCepsilon activation, and hepatic insulin resistance.
Zhang
Dongyan
D
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Liu
Zhen-Xiang
ZX
Choi
Cheol Soo
CS
Tian
Liqun
L
Kibbey
Richard
R
Dong
Jianying
J
Cline
Gary W
GW
Wood
Philip A
PA
Shulman
Gerald I
GI
D000214:Acyl Coenzyme A / Q000378:metabolism; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency*; D000818:Animals; D002151:Calorimetry; D002247:Carbon Isotopes; D004075:Diglycerides / Q000096:biosynthesis; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000096:biosynthesis
D000214:Acyl Coenzyme A; D002247:Carbon Isotopes; D004075:Diglycerides; D007328:Insulin; D014280:Triglycerides; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D051744:Protein Kinase C-epsilon; D005947:Glucose