Journal Article

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

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

2020

Overview

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. Human antigen R (HuR) is a RNA binding protein involved in the regulation of many cellular functions. Here the authors show that, hepatocyte specific deletion of HuR exacerbates high-fat diet-induced NAFLD in mice by regulating transcripts involved in lipid transport and ATP synthesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 38 / 631/337 / 692/308 / 692/4017 / Adenosine Triphosphate - biosynthesis / Animals / Antigens / Apolipoprotein B-100 - genetics / Apolipoprotein B-100 - metabolism / Cytochromes c - genetics / Cytochromes c - metabolism / Diet / 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 / Fatty liver / Hepatocytes / High fat diet / Homeostasis / Humanities and Social Sciences / HuR protein / Lipid Metabolism / Lipids / Liver / Liver - metabolism / Liver diseases / Male / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Non-alcoholic Fatty Liver Disease - etiology / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - metabolism / Proteins / RNA Precursors / RNA-binding protein / Science / Science (multidisciplinary) / Splicing / Synthesis