Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy.
Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy.
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DOI：
10.1016/j.cmet.2009.01.002
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发表时间：
2009-02
期刊：
影响因子：
29
通讯作者：
Garg A
中科院分区：
文献类型：
--
作者：
Cortés VA;Curtis DE;Sukumaran S;Shao X;Parameswara V;Rashid S;Smith AR;Ren J;Esser V;Hammer RE;Agarwal AK;Horton JD;Garg A
1-酰基甘油-3-磷酸-O-酰基转移酶2（AGPAT 2）突变可导致先天性全身性脂肪营养不良。为了理解与AGPAT 2缺陷相关的代谢并发症的分子机制，产生了Agpat 2缺失小鼠。Agpat 2 −/−小鼠发生严重的脂肪代谢障碍，影响白色和棕色脂肪组织，严重的胰岛素抵抗，糖尿病和肝脂肪变性。在Agpat 2 −/−小鼠肝脏中，脂肪生成基因的表达和从头脂肪酸生物合成的速率增加了约4倍。单酰基甘油酰基转移酶亚型1的mRNA和蛋白质水平在Agpat 2 −/−小鼠的肝脏中显著增加，表明甘油三酯生物合成的替代单酰基甘油途径在缺乏AGPAT 2的情况下被激活。在Agpat 2 −/−小鼠中，喂食无脂饮食可使肝脏甘油三酯降低约50%。这些观察结果表明，饮食脂肪和肝脏甘油三酯生物合成通过一种新的单酰基甘油途径可能有助于肝脂肪变性Agpat 2 −/−小鼠。
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, severe 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 novel monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2−/− mice.
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