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

被引:185
作者
Cortes, Victor A. [2 ]
Curtis, David E. [2 ,3 ]
Sukumaran, Suja [1 ]
Shao, Xinli [1 ]
Parameswara, Vinay
Rashid, Shirya [2 ]
Smith, Amy R. [2 ]
Ren, Jimin [4 ]
Esser, Victoria
Hammer, Robert E. [5 ]
Agarwal, Anil K.
Horton, Jay D. [2 ,6 ]
Garg, Abhimanyu [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Div Nutr & Metab Dis, Dept Internal Med, Ctr Human Nutr, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Dept Surg, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Dept Adv Imaging, Dallas, TX 75390 USA
[5] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[6] Univ Texas SW Med Ctr Dallas, Div Gastroenterol, Dept Internal Med, Dallas, TX 75390 USA
基金
美国国家卫生研究院;
关键词
LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE; ELEMENT-BINDING PROTEIN; TRANSGENIC MICE; LIPID-SYNTHESIS; MONOACYLGLYCEROL ACYLTRANSFERASE; FUNCTIONAL-CHARACTERIZATION; ENZYMATIC-ACTIVITY; GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE; TISSUE DISTRIBUTION; DIABETES-MELLITUS;
D O I
10.1016/j.cmet.2009.01.002
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 similar to 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 similar to 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.
引用
收藏
页码:165 / 176
页数:12
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