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

Mi Tian; Jingjing Wang; Shangming Liu; Xinyun Li; Jingyuan Li; Jianmin Yang; Cheng Zhang; Wencheng Zhang

doi:10.1038/s41419-021-03514-0

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

Cell Death Dis. 2021 Mar 4;12(3):236. doi: 10.1038/s41419-021-03514-0.

Authors

Mi Tian^{1

2}, Jingjing Wang³, Shangming Liu⁴, Xinyun Li¹, Jingyuan Li¹, Jianmin Yang¹, Cheng Zhang¹, Wencheng Zhang^{5

6}

Affiliations

¹ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Shandong, China.
³ Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Shandong University, Shandong, China.
⁴ Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Shandong, China.
⁵ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. zhangwencheng@sdu.edu.cn.
⁶ Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Shandong, China. zhangwencheng@sdu.edu.cn.

Abstract

The liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuR^LKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3' untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuR^LKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Binding Sites
Blood Glucose / metabolism
Cell Line
Diet, High-Fat
Disease Models, Animal
ELAV-Like Protein 1 / genetics
ELAV-Like Protein 1 / metabolism*
Energy Metabolism*
Insulin Resistance*
Lipid Metabolism*
Liver / enzymology*
Liver / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease / enzymology*
Non-alcoholic Fatty Liver Disease / genetics
Non-alcoholic Fatty Liver Disease / pathology
Non-alcoholic Fatty Liver Disease / prevention & control
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism*
RNA Stability
RNA, Messenger / genetics
RNA, Messenger / metabolism

Substances

3' Untranslated Regions
Blood Glucose
ELAV-Like Protein 1
ELAVL1 protein, human
Elavl1 protein, mouse
RNA, Messenger
PTEN Phosphohydrolase
PTEN protein, human
Pten protein, mouse