Zhang Yuan-Li, Hernandez-Ono Antonio, Siri Patty, Weisberg Stuart, Conlon Donna, Graham Mark J, Crooke Rosanne M, Huang Li-Shin, Ginsberg Henry N
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
J Biol Chem. 2006 Dec 8;281(49):37603-15. doi: 10.1074/jbc.M604709200. Epub 2006 Sep 12.
Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064-46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPARgamma2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPARgamma, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPARgamma antisense oligonucleotide resulted in dramatic reductions of both PPARgamma1 and PPARgamma2 mRNA, PPARgamma2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPARgamma2. The mechanism whereby hepatic Ppargamma2 gene expression is increased and how PPARgamma2 stimulates lipogenesis is under investigation.
与仅表达载脂蛋白B（apoB）的小鼠相比，胰岛素抵抗的apoB/BAT缺失小鼠出现高甘油三酯血症，这是因为极低密度载脂蛋白B（apoB）和甘油三酯的组装及分泌增加（西里，P.，坎德拉，N.，科，C.，张，Y.，尤苏夫扎伊，S.，金斯伯格，H.N.，以及黄，L.S.（2001年）《生物化学杂志》276卷，46064 - 46072页）。尽管极低密度脂蛋白分泌增加，但apoB/BAT缺失小鼠仍有脂肪肝。我们发现，与apoB小鼠相比，apoB/BAT缺失小鼠肝脏中关键生脂酶、乙酰辅酶A羧化酶、脂肪酸合酶和硬脂酰辅酶A去饱和酶 - 1的mRNA水平升高，提示apoB/BAT缺失小鼠的生脂作用增强。通过测定氚水掺入脂肪酸的情况证实了这一点。在apoB/BAT缺失小鼠中，生脂转录因子SREBP - 1c（固醇反应元件结合蛋白1c）的肝脏mRNA以及成熟形式的SREBP - 1蛋白的核水平均未升高。相比之下，apoB/BAT缺失小鼠肝脏中过氧化物酶体增殖物激活受体2（PPARγ2）的mRNA和蛋白水平特异性升高，PPARγ的两个靶标CD36和aP2的肝脏mRNA水平也升高。用PPARγ反义寡核苷酸腹腔注射apoB/BAT缺失小鼠4周，导致PPARγ1和PPARγ2的mRNA、PPARγ2蛋白以及脂肪酸合酶和乙酰辅酶A羧化酶的mRNA水平显著降低。这些变化与肝脏从头脂肪生成减少和肝脏甘油三酯浓度降低有关。我们得出结论，apoB/BAT缺失小鼠的肝脏脂肪变性与肝脏脂肪生成速率升高有关，而这直接与肝脏PPARγ2表达增加相关。肝脏Pparγ2基因表达增加的机制以及PPARγ2如何刺激脂肪生成正在研究中。
