Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy

Víctor A. Cortés, David E. Curtis, Suja Sukumaran, Xinli Shao, Vinay Parameswara, Shirya Rashid, Amy R. Smith, Jimin Ren, Victoria Esser, Robert E Hammer, Anil K Agarwal, Jay D Horton, Abhimanyu Garg

Research output: Contribution to journalArticle

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Abstract

Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2-/- mice develop severe lipodystrophy affecting both white and brown adipose tissue, extreme insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ∼4-fold in Agpat2-/- mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2-/- mice, suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ∼50% in Agpat2-/- mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2-/- mice.

Original languageEnglish (US)
Pages (from-to)165-176
Number of pages12
JournalCell Metabolism
Volume9
Issue number2
DOIs
StatePublished - Feb 4 2009

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1-Acylglycerol-3-Phosphate O-Acyltransferase
Congenital Generalized Lipodystrophy
Insulin Resistance
Liver
Monoglycerides
Triglycerides
Lipodystrophy
White Adipose Tissue
Fat-Restricted Diet
Brown Adipose Tissue
Dietary Fats
Protein Isoforms
Fatty Acids
Gene Expression
Messenger RNA
Mutation

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy. / Cortés, Víctor A.; Curtis, David E.; Sukumaran, Suja; Shao, Xinli; Parameswara, Vinay; Rashid, Shirya; Smith, Amy R.; Ren, Jimin; Esser, Victoria; Hammer, Robert E; Agarwal, Anil K; Horton, Jay D; Garg, Abhimanyu.

In: Cell Metabolism, Vol. 9, No. 2, 04.02.2009, p. 165-176.

Research output: Contribution to journalArticle

Cortés, Víctor A. ; Curtis, David E. ; Sukumaran, Suja ; Shao, Xinli ; Parameswara, Vinay ; Rashid, Shirya ; Smith, Amy R. ; Ren, Jimin ; Esser, Victoria ; Hammer, Robert E ; Agarwal, Anil K ; Horton, Jay D ; Garg, Abhimanyu. / Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy. In: Cell Metabolism. 2009 ; Vol. 9, No. 2. pp. 165-176.
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