RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism
RNA-binding protein ZFP36L1 maintains posttranscriptional regulation of bile acid metabolism
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DOI：
10.1172/jci94029
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发表时间：
2017-10-02
影响因子：
15.9
通讯作者：
Vallim, Thomas Q. de Aguiar
中科院分区：
文献类型：
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作者：
Tarling, Elizabeth J.;Clifford, Bethan L.;Vallim, Thomas Q. de Aguiar
胆汁酸不仅作为去污剂促进脂质吸收，而且作为信号分子激活核受体法尼醇X受体（FXR）。FXR激动剂由于其降脂和降血脂特性，目前正在评估其作为许多肝脏疾病的治疗剂。FXR对于维持胆汁酸稳态和防止胆汁酸积累也是必不可少的。胆汁酸升高激活FXR，进而通过降低胆汁酸合成基因（包括胆固醇7 α-羟化酶（Cyp 7a 1））的mRNA水平来关闭胆汁酸合成。在这里，我们表明，FXR激活触发一个快速的转录后机制降解Cyp 7a 1 mRNA。我们鉴定了RNA结合蛋白Zfp 36 l1作为FXR靶基因，并确定了ZFP 36 L1功能的获得和丧失在体内可调节Cyp 7a 1 mRNA和胆汁酸水平。此外，我们发现缺乏肝脏ZFP 36 L1的小鼠受到保护，免于饮食诱导的肥胖和脂肪变性。在ZFP 36 L1缺陷小鼠中观察到的肥胖减少和抗脂肪变性作用伴随着脂质吸收受损，这与胆汁酸代谢的改变一致。因此，胆汁酸代谢的ZFP 36 L1依赖性调节是肥胖和脂肪肝的重要代谢贡献者。
Bile acids function not only as detergents that facilitate lipid absorption but also as signaling molecules that activate the nuclear receptor farnesoid X receptor (FXR). FXR agonists are currently being evaluated as therapeutic agents for a number of hepatic diseases due to their lipid-lowering and antiinflammatory properties. FXR is also essential for maintaining bile acid homeostasis and prevents the accumulation of bile acids. Elevated bile acids activate FXR, which in turn switches off bile acid synthesis by reducing the mRNA levels of bile acid synthesis genes, including cholesterol 7 alpha-hydroxylase (Cyp7a1). Here, we show that FXR activation triggers a rapid posttranscriptional mechanism to degrade Cyp7a1 mRNA. We identified the RNA-binding protein Zfp36l1 as an FXR target gene and determined that gain and loss of function of ZFP36L1 reciprocally regulate Cyp7a1 mRNA and bile acid levels in vivo. Moreover, we found that mice lacking hepatic ZFP36L1 were protected from diet-induced obesity and steatosis. The reduced adiposity and antisteatotic effects observed in ZFP36L1-deficient mice were accompanied by impaired lipid absorption that was consistent with altered bile acid metabolism. Thus, the ZFP36L1-dependent regulation of bile acid metabolism is an important metabolic contributor to obesity and hepatosteatosis.