ZFP36L1 is a post‐transcriptional regulator of 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 agonists are currently promising therapeutic agents to treat non‐alcoholic steatohepatitis (NASH), a significant risk factor for cardiovascular disease. FXR is the central rheostat of bile acid metabolism, and activation of FXR decreases the mRNA levels of several bile acid synthetic genes, including the expression of the gene encoding the rate‐limiting enzyme of bile acid synthesis, Cyp7a1. We show that Cyp7a1 mRNA levels were rapidly reduced after pharmacologic FXR activation in wild‐type, but not Fxr−/− or liver‐specific Fxr knockout mice (FxrL‐KO). The rapid decrease in Cyp7a1 mRNA suggested a previously unidentified post‐transcriptional mechanism. To identify the molecular mechanism, we used FXR ChIP‐Seq and RNA‐Seq to identify the RNA binding protein Zfp36l1 as a novel FXR target gene. We showed that FXR activation using synthetic and endogenous agonists increases ZFP36L1 mRNA and protein levels in wild‐type, but not Fxr−/− mice. Further, the increased ZFP36L1 mRNA and protein was observed 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 Cyp7a1 mRNA and protein and decreased bile acid levels. To complement our gain‐of‐function studies, we generated liver‐specific Zfp36l1 knockout mice (Zfp36l1L‐KO) and we show that loss of Zfp36l1 resulted in elevated Cyp7a1 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 Zfp36l1 resulted in more broad metabolic dysfunction. Western diet fed Zfp36l1L‐KO mice had reduced body weight gain, specifically in adipose tissue depots compared to littermate Zfp36l1flox‐flox mice. In addition, Zfp36l1L‐KO mice also had reduced hepatic steatosis, without any differences in energy expenditure compared to littermate Zfp36l1flox‐flox mice. The differences in adiposity and steatosis were attributed to reduced lipid absorption, as Zfp36l1L‐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 Cyp7a1 and bile acid metabolism but may also have wider implications in diseases such as obesity and hepatosteatosis, which are both significant risk factors for cardiovascular disease.Support or Funding InformationNIH grants HL118161 and HL136543 to E.J.T., and AHA grant SDG18440015 and NIH grants HL122677 and DK102559 to T.Q.de A.V.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.