Abstract 402: Post-transcriptional Regulation of Bile Acid Metabolism by the RNA binding protein ZFP36L1

Abstract

Bile acids are detergents and important signaling molecules that activate the nuclear receptor FXR to control key metabolic processes, including feedback mechanisms to maintain bile acid homeostasis. Activation of FXR decreases the mRNA levels of several bile acid synthetic genes, including the rate-limiting enzyme Cyp7a1 . Here we show that Cyp7a1 mRNA levels are very rapidly reduced following FXR activation, indicative of a post-transcriptional mechanism. We identify the RNA binding protein Zfp36l1 as an FXR target gene and show that hepatic overexpression of ZFP36L1 in mice decreases Cyp7a1 mRNA levels. In contrast, Zfp36l1 L -KO mice have increased levels of Cyp7a1 mRNA and biliary bile acids as well as reduced plasma cholesterol levels. Zfp36l1 L -KO mice fed a Western diet have reduced diet-induced obesity and steatosis, likely due to impaired lipid absorption, consistent with increased Cyp7a1 levels. Thus, the ZFP36L1-dependent regulation of bile acid metabolism is an important metabolic contributor of dyslipidemia, obesity and hepatosteatosis.