Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance.

Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Research Abstract Details 

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Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Abstract Text:

Dongyan Zhang,Zhen-Xiang Liu,Cheol Soo Choi,Liqun Tian,Richard Kibbey,Jianying Dong,Gary W Cline,Philip A Wood,Gerald I Shulman,

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.

Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Publishing Authors By Initials

D Zhang,ZX Liu,CS Choi,L Tian,R Kibbey,J Dong,GW Cline,PA Wood,GI Shulman,

For similar lipids: glycerides: triglycerides research abstracts see: lipids: glycerides: triglycerides research

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Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 104

Page Numbers: 17075-80

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 0027-8424

DAY: 16

MONTH: 10

YEAR: 2007

Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7505876

Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Keywords Mesh Terms:

KEYWORDS: Triglycerides

MESH TERMS: biosynthesis

Chemical & Substance for Abstract: Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Information

Substance Name: Protein Kinase C-epsilon

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance.

AFFILIATION: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.

Country: United States

AGENCY: United States NIDDK

GRANT: U24 DK 59635

ACRONYM: DK

MEDLINETA: Proc Natl Acad Sci U S A

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