Abstract 202: Zfp36l1 is a Post transcriptional Regulator of Hepatic Bile Acid and Lipid Metabolism

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. FXR is the central rheostat of bile acid metabolism, and activation of FXR decreases the mRNA levels of bile acid synthetic genes, including Cyp 7 a 1 , the gene encoding the rate-limiting enzyme of bile acid synthesis. We show that Cyp 7 a 1 mRNA levels were rapidly reduced after pharmacologic FXR activation in wild-type, but not Fxr – / – or liver-specific Fxr knockout mice ( Fxr L - KO ). The rapid decrease in Cyp 7 a 1 mRNA suggested a previously unidentified post-transcriptional mechanism. To identify the mechanism, we used synthetic and endogenous FXR agonists and found the RNA binding protein ZFP36L1 as a novel FXR target gene. ZFP36L1 mRNA and protein levels were increased as early as 30 minutes after FXR activation. ZFP36L1 is a bona - fide RNA binding protein that promotes degradation of mRNA targets by binding to AU-rich elements (AREs) in the 3’ UTR. We generated in vivo and in vitro gain-of-function models and we used reporter assays to show that ZFP36L1 targets the Cyp7a1 UTR . In mice, hepatic overexpression of ZFP36L1 decreased Cyp 7 a 1 mRNA and protein and decreased bile acid levels. To complement our gain-of-function studies, we generated liver-specific Zfp 36 l 1 knockout mice ( Zfp 36 l 1 L - KO ) and we show that loss of Zfp 36 l 1 resulted in elevated Cyp 7 a 1 mRNA and protein, and increased bile acid levels. Given that bile acids are important metabolites that control lipid absorption and signaling, we investigated whether loss of hepatic Zfp 36 l 1 resulted in more broad metabolic dysfunction. Western diet fed Zfp 36 l 1 L - KO mice had reduced body weight gain, specifically in adipose tissue depots compared to littermate Zfp 36 l 1 flox-flox mice. The differences in adiposity and steatosis were attributed to reduced lipid absorption, as Zfp 36 l 1 L - KO mice have increased fecal caloric content and reduced triglyceride absorption as determined by an intragastric fat tolerance test. The decreased lipid absorption is consistent with an altered bile acid metabolism. Thus, we have identified a novel pathway that controls Cyp 7 a 1 and bile acid metabolism but may also have wider implications in diseases such as obesity and hepatosteatosis.