Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease

Background: Liver plays an important role in lipid and glucose metabolism. Human antigen R (HuR) as an RNA regulator protein participates in many disease processes. Here, we investigated the specific role of HuR in hepatic steatosis and glucose metabolism. Methods: We investigated the level of HuR in liver from mice fed a normal chow diet (NCD) and high fat diet (HFD). Liver specific HuR knockout (HuRLKO) mice were generated and challenged with an HFD. Lipid levels and glucose metabolism index were examined. Findings: HuR was downregulated in livers of HFD-fed mice. HuRLKO mice showed exacerbated HFD-induced hepatic steatosis but improved glucose tolerance as compared with controls. Consistently, HuR inhibited lipid accumulation in hepatocytes. Mechanically, HuR could bind to the mRNA of phosphatase and tensin homology deleted on chromosome 10 (PTEN), thus increasing their stability and translation. Finally, PTEN over-expression alleviated HFD-induced hepatic steatosis in HuRLKO mice. Interpretation: HuR modulates lipid and glucose metabolism through regulating PTEN expression. Funding Statement: This work was supported by the National Natural Science Foundation of China (no. 81970198, 81770473) and the Taishan Scholar Project of Shandong Province of China (no. tsqn20161066). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The animal experiment was approved by the Animal Care Committee of Shandong University and was performed in compliance with the Animal Management Rules of the Chinese Ministry of Health (Document No. 55, 2001). All procedures conformed to the guidelines from the NIH Guide for the Care and Use of Laboratory Animals.