Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation
Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation
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DOI：
10.1172/jci25256
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Postic, C
中科院分区：
文献类型：
--
作者：
Dentin, R;Benhamed, F;Postic, C
膳食多不饱和脂肪酸(PUFAs)是肝脏糖酵解和脂肪生成的有效抑制剂。近年来，糖反应元件结合蛋白参与了葡萄糖对糖酵解和生脂基因的调控，其中包括编码L-丙酮酸激酶(L-PK)和脂肪酸合成酶(Fas)的基因。本研究旨在探讨CHREBP在多不饱和脂肪酸抑制L-PK和Fas基因表达中的作用。我们在小鼠体内和体外证明，多不饱和脂肪酸[亚油酸(C18：2)、二十碳五酸(C20：5)和二十二碳六烯酸(C22：6)]通过增加ChREBP mRNA的衰变和改变ChREBP从胞浆到细胞核的移位来抑制ChREBP活性，而不依赖于AMP激活的蛋白激酶的激活，先前被证明调节ChREBP活性。相反，饱和[硬脂酸(C18)]和单不饱和脂肪酸[油酸(C18：1)]没有影响。由于通过磷酸戊糖途径的葡萄糖代谢是ChREBP核转位的决定因素，多不饱和脂肪酸饮食导致的木糖5-磷酸浓度的降低有利于PUFA介导的对ChREBP转位的抑制。此外，在培养的肝细胞中过表达核ChREBP亚型显著降低了多不饱和脂肪酸对L-PK和Fas基因表达的抑制。我们的结果表明，多不饱和脂肪酸对这些基因的抑制作用主要是由ChREBP核易位的改变引起的。总之，我们描述了一种新的机制来解释多不饱和脂肪酸对L-PK和Fas编码基因的抑制作用，并证明ChREBP是一个关键的转录因子，负责协调多不饱和脂肪酸对糖酵解和成脂基因的抑制。
Dietary polyunsaturated fatty acids (PUFAs) are potent inhibitors of hepatic glycolysis and lipogenesis. Recently, carbohydrate-responsive element-binding protein (ChREBP) was implicated in the regulation by glucose of glycolytic and lipogenic genes, including those encoding L-pyruvate kinase (L-PK) and fatty acid synthase (FAS). The aim of our study was to assess the role of ChREBP in the control of L-PK and FAS gene expression by PUFAs. We demonstrated in mice, both in vivo and in vitro, that PUFAs [linoleate (C18:2), eicosapentanoic acid (C20:5), and docosahexaenoic acid (C22:6)] suppressed ChREBP activity by increasing ChREBP mRNA decay and by altering ChREBP translocation from the cytosol to the nucleus, independently of an activation of the AMP-activated protein kinase, previously shown to regulate ChREBP activity. In contrast, saturated [stearate (C18)] and monounsaturated fatty acids [oleate (C18:1)] had no effect. Since glucose metabolism via the pentose phosphate pathway is determinant for ChREBP nuclear translocation, the decrease in xylulose 5-phosphate concentrations caused by a PUFA diet favors a PUFA-mediated inhibition of ChREBP translocation. In addition, overexpression of a constitutive nuclear ChREBP isoform in cultured hepatocytes significantly reduced the PUFA inhibition of both L-PK and FAS gene expression. Our results demonstrate that the suppressive effect of PUFAs on these genes is primarily caused by an alteration of ChREBP nuclear translocation. In conclusion, we describe a novel -mechanism to explain the inhibitory effect of PUFAs on the genes encoding L-PK and FAS and demonstrate that ChREBP is a pivotal transcription factor responsible for coordinating the PUFA suppression of glycolytic and lipogenic genes.