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 7α-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.

中文翻译：

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RNA结合蛋白ZFP36L1维持胆汁酸代谢的转录后调节


胆汁酸不仅可以作为促进脂质吸收的去垢剂，还可以作为激活核受体法尼醇 X 受体 (FXR) 的信号分子。由于 FXR 激动剂具有降脂和抗炎特性，目前正在评估其作为多种肝脏疾病的治疗药物。 FXR 对于维持胆汁酸稳态并防止胆汁酸积累也至关重要。胆汁酸升高会激活 FXR，FXR 进而通过降低胆汁酸合成基因（包括胆固醇 7α-羟化酶 ( Cyp7a1 )）的 mRNA 水平来关闭胆汁酸合成。在这里，我们表明 FXR 激活触发快速转录后机制来降解Cyp7a1 mRNA。我们将 RNA 结合蛋白Zfp36l1确定为 FXR 靶基因，并确定 ZFP36L1 功能的获得和丧失可相互调节体内Cyp7a1 mRNA 和胆汁酸水平。此外，我们发现缺乏肝脏 ZFP36L1 的小鼠可以免受饮食引起的肥胖和脂肪变性的影响。在 ZFP36L1 缺陷小鼠中观察到的肥胖和抗脂肪变作用减少伴随着脂质吸收受损，这与胆汁酸代谢的改变一致。因此，ZFP36L1 依赖性胆汁酸代谢调节是肥胖和肝脂肪变性的重要代谢因素。