PPARγ2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes
PPARγ2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes
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DOI：
10.1152/ajpendo.00513.2004
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发表时间：
2005-06-01
影响因子：
5.1
通讯作者：
Farmer, SR
中科院分区：
文献类型：
--
作者：
Schadinger, SE;Bucher, NLR;Farmer, SR
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）被认为是脂肪细胞分化的主要调节因子之一。PPAR γ 2在成熟脂肪细胞中大量表达，并且在发生脂肪肝的动物的肝脏中升高。本研究的目的是确定过氧化物酶体增殖物激活受体γ 2诱导肝细胞脂质蓄积的能力，并描述驱动这一过程的分子机制。使用肝细胞系AML-12来产生稳定表达PPAR γ 2的细胞系。油红O染色显示，PPAR γ 2诱导肝细胞中的脂质积聚。这种表型伴随着几种脂肪形成和脂肪形成基因的选择性上调，包括脂肪分化相关蛋白（ADRP）、脂肪细胞脂肪酸结合蛋白4、固醇调节元件结合蛋白-1（SREBP-1）、脂肪酸合成酶（FAS）和乙酰辅酶A羧化酶，已知这些基因的表达水平在ob/ob小鼠脂肪变性肝脏中增加。此外，SREBP-1和FAS的PPAR γ 2调节诱导与肝细胞中从头三酰甘油合成的增加平行。在不存在外源性脂质的情况下，用曲格列酮培养肝细胞可进一步增强三酰甘油合成和脂质蓄积。这些结果与脂滴蛋白ADRP的增加相对应，并且数据表明ADRP用于包被肝细胞中的脂滴，如通过共聚焦显微镜观察到的。综上所述，这些观察结果表明，PPAR γ 2作为肝细胞脂肪变性的诱导剂的作用，并表明这种现象是通过诱导调节从头脂质合成的途径发生的。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is considered to be one of the master regulators of adipocyte differentiation. PPAR gamma 2 is abundantly expressed in mature adipocytes and is elevated in the livers of animals that develop fatty livers. The aim of this study was to determine the ability of PPAR gamma 2 to induce lipid accumulation in hepatocytes and to delineate molecular mechanisms driving this process. The hepatic cell line AML-12 was used to generate a cell line stably expressing PPAR gamma 2. Oil Red O staining revealed that PPAR gamma 2 induces lipid accumulation in hepatocytes. This phenotype is accompanied by a selective upregulation of several adipogenic and lipogenic genes including adipose differentiation-related protein (ADRP), adipocyte fatty acid-binding protein 4, sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS), and acetyl-CoA carboxylase, genes whose expression levels are known to increase in steatotic livers of ob/ob mice. Furthermore, the PPAR gamma 2-regulated induction of both SREBP-1 and FAS parallels an increase in de novo triacylglycerol synthesis in hepatocytes. Triacylglycerol synthesis and lipid accumulation are further enhanced by culturing hepatocytes with troglitazone in the absence of exogenous lipids. These results correspond with an increase in the lipid droplet protein, ADRP, and the data demonstrate that ADRP functions to coat lipid droplets in hepatocytes as observed by confocal microscopy. Taken together, these observations propose a role for PPAR gamma 2 as an inducer of steatosis in hepatocytes and suggest that this phenomenon occurs through an induction of pathways regulating de novo lipid synthesis.