Hepatic HuR modulates lipid homeostasis in response to high-fat diet

Zhuojun Zhang; Chen Zong; Mingyang Jiang; Han Hu; Xiaolei Cheng; Juhua Ni; Xia Yi; Bin Jiang; Feng Tian; Ming-Wen Chang; Wen Su; Lijun Zhu; Jinfan Li; Xueping Xiang; Congxiu Miao; Myriam Gorospe; Rafael de Cabo; Yali Dou; Zhenyu Ju; Jichun Yang; Changtao Jiang; Zhongzhou Yang; Wengong Wang

doi:10.1038/s41467-020-16918-x

Hepatic HuR modulates lipid homeostasis in response to high-fat diet

Nat Commun. 2020 Jun 16;11(1):3067. doi: 10.1038/s41467-020-16918-x.

Authors

Zhuojun Zhang^#¹, Chen Zong^#¹, Mingyang Jiang², Han Hu¹, Xiaolei Cheng¹, Juhua Ni¹, Xia Yi¹, Bin Jiang¹, Feng Tian³, Ming-Wen Chang⁴, Wen Su⁵, Lijun Zhu⁶, Jinfan Li⁷, Xueping Xiang⁷, Congxiu Miao⁸, Myriam Gorospe⁴, Rafael de Cabo⁹, Yali Dou¹⁰, Zhenyu Ju¹¹, Jichun Yang¹², Changtao Jiang¹², Zhongzhou Yang¹³, Wengong Wang¹⁴

Affiliations

¹ Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China.
² State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, 210061, Nanjing, China.
³ Department of Laboratory Animal Science, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China.
⁴ Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd., Baltimore, MD, 21224, USA.
⁵ Department of Pathology, Shenzhen University Health Science Center, 519060, Shenzhen, China.
⁶ Zhejiang Provincial Key laboratory of Pancreatic Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, China.
⁷ Department of Pathology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, 310009, Hangzhou, China.
⁸ Institute of Reproduction and Genetics, Changzhi Medical College, 046000, Changzhi, China.
⁹ Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
¹⁰ Department of Pathology and Biological Chemistry, University of Michigan, 1301 Catherine Street, Ann Arbor, MI, 48105, USA.
¹¹ Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, 510632, Guangzhou, China.
¹² Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, P.R. China.
¹³ State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, 210061, Nanjing, China. [email protected].
¹⁴ Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, 100191, Beijing, China. [email protected].

^# Contributed equally.

Abstract

Lipid transport and ATP synthesis are critical for the progression of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) forms complexes with NAFLD-relevant transcripts. It associates with intron 24 of Apob pre-mRNA, with the 3'UTR of Uqcrb, and with the 5'UTR of Ndufb6 mRNA, thereby regulating the splicing of Apob mRNA and the translation of UQCRB and NDUFB6. Hepatocyte-specific HuR knockout reduces the expression of APOB, UQCRB, and NDUFB6 in mice, reducing liver lipid transport and ATP synthesis, and aggravating high-fat diet (HFD)-induced NAFLD. Adenovirus-mediated re-expression of HuR in hepatocytes rescues the effect of HuR knockout in HFD-induced NAFLD. Our findings highlight a critical role of HuR in regulating lipid transport and ATP synthesis.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / biosynthesis
Animals
Apolipoprotein B-100 / genetics
Apolipoprotein B-100 / metabolism
Cytochromes c / genetics
Cytochromes c / metabolism
Diet, High-Fat / adverse effects*
ELAV-Like Protein 1 / genetics
ELAV-Like Protein 1 / metabolism*
Electron Transport Chain Complex Proteins / genetics
Electron Transport Complex I / genetics
Homeostasis
Lipid Metabolism*
Liver / metabolism*
Male
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease / etiology
Non-alcoholic Fatty Liver Disease / genetics
Non-alcoholic Fatty Liver Disease / metabolism*
RNA Precursors

Substances

Apob protein, mouse
Apolipoprotein B-100
ELAV-Like Protein 1
Elavl1 protein, mouse
Electron Transport Chain Complex Proteins
RNA Precursors
Uqcrb protein, mouse
Adenosine Triphosphate
Cytochromes c
Electron Transport Complex I
Ndufb6 protein, mouse