Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis
Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis
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DOI：
10.1073/pnas.1203218109
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发表时间：
2012-08-21
影响因子：
11.1
通讯作者：
Kim, Jae-Woo
中科院分区：
文献类型：
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作者：
Lee, Yoo Jeong;Ko, Eun Hee;Kim, Jae-Woo
最近，肝脏过氧化物酶体增殖物激活受体（PPAR）γ与肝脏脂质积累有关。我们发现，与 C57BL/6 (B6) 小鼠相比，C3H 小鼠品系在肝脏中不表达 PPAR γ，并且在接受高脂肪饮食时，能够抵抗肝脂肪变性。将腺病毒 PPAR γ 2 注射到 B6 和 C3H 小鼠中会引起肝脏脂肪变性，微阵列分析表明肝脏 PPAR γ 2 表达与参与脂肪酸转运和甘油三酯合成途径的基因相关。特别是，肝脏 PPAR gamma 2 表达显着增加单酰基甘油 O-酰基转移酶 1 (MGAT1) 的表达。通过荧光素酶测定、电泳迁移率变动测定以及染色质免疫沉淀测定进行的启动子分析表明，PPAR gamma 2 直接调节 MGAT1 启动子活性。培养的肝细胞中 MGAT1 的过表达增强了甘油三酯的合成，但不增加 PPAR γ 的表达。重要的是，在肝脏中敲低 MGAT1 可显着减少 12 周龄高脂喂养小鼠以及 ob/ob 小鼠的肝脏脂肪变性，同时伴有体重减轻和葡萄糖耐量改善。这些结果表明，由肝 PPAR γ 诱导的 MGAT1 通路对于饮食诱导的肥胖期间肝脂肪变性的发展至关重要。
Recently, hepatic peroxisome proliferator-activated receptor (PPAR)gamma has been implicated in hepatic lipid accumulation. We found that the C3H mouse strain does not express PPAR gamma in the liver and, when subject to a high-fat diet, is resistant to hepatic steatosis, compared with C57BL/6 (B6) mice. Adenoviral PPAR gamma 2 injection into B6 and C3H mice caused hepatic steatosis, and microarray analysis demonstrated that hepatic PPAR gamma 2 expression is associated with genes involved in fatty acid transport and the triglyceride synthesis pathway. In particular, hepatic PPAR gamma 2 expression significantly increased the expression of monoacylglycerol O-acyltransferase 1 (MGAT1). Promoter analysis by luciferase assay and electrophoretic mobility shift assay as well as chromatin immunoprecipitation assay revealed that PPAR gamma 2 directly regulates the MGAT1 promoter activity. The MGAT1 overexpression in cultured hepatocytes enhanced triglyceride synthesis without an increase of PPAR gamma expression. Importantly, knockdown of MGAT1 in the liver significantly reduced hepatic steatosis in 12-wk-old high-fat-fed mice as well as ob/ob mice, accompanied by weight loss and improved glucose tolerance. These results suggest that the MGAT1 pathway induced by hepatic PPAR gamma is critically important in the development of hepatic steatosis during diet-induced obesity.