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.
Elizabeth J. Tarling, Bethan L. Clifford, Joan Cheng, Pauline Morand, Angela Cheng, Ellen Lester, Tamer Sallam, Martin Turner, Thomas Q. de Aguiar Vallim
FXR activation leads to rapid changes in gene expression.