IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs

Jie-Mei Wang; Yining Qiu; Zhao Yang; Hyunbae Kim; Qingwen Qian; Qinghua Sun; Chunbin Zhang; Lei Yin; Deyu Fang; Sung Hong Back; Randal J Kaufman; Ling Yang; Kezhong Zhang

doi:10.1126/scisignal.aao4617

Back

IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs

Journal article

Open access

Peer reviewed

IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs

Jie-Mei Wang, Yining Qiu, Zhao Yang, Hyunbae Kim, Qingwen Qian, Qinghua Sun, Chunbin Zhang, Lei Yin, Deyu Fang, Sung Hong Back, …

Science signaling, Vol.11(530), p.eaao4617

05/15/2018

DOI: 10.1126/scisignal.aao4617

PMCID: PMC6075656

PMID: 29764990

Files and links (1)

url

https://doi.org/10.1126/scisignal.aao4617View

Published (Version of record) Open Access

Abstract

Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. We found that IRE1α was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1α processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1α promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1α and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator-activated receptor α (PPARα) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1α deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1α maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1α-UPR pathway under acute ER stress.

Sirtuin 1 - metabolism

Fatty Liver - pathology

Humans

Middle Aged

Diet, High-Fat - adverse effects

MicroRNAs - metabolism

Hepatocytes - metabolism

Sirtuin 1 - genetics

Endoribonucleases - physiology

Hepatocytes - cytology

Protein-Serine-Threonine Kinases - metabolism

Fatty Liver - metabolism

Endoribonucleases - metabolism

Protein-Serine-Threonine Kinases - physiology

Mice, Inbred C57BL

Cells, Cultured

Fatty Liver - prevention & control

Gene Expression Regulation

Insulin Resistance

PPAR alpha - genetics

Unfolded Protein Response

Mice, Knockout

Animals

Mice

MicroRNAs - genetics

Lipids - analysis

PPAR alpha - metabolism

Fatty Liver - etiology

Details

Title: Subtitle: IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs
Creators: Jie-Mei Wang - Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, MI 48201, USA
Yining Qiu - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Zhao Yang - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Hyunbae Kim - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Qingwen Qian - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Qinghua Sun - Division of Environmental Health Sciences, College of Public Health, Ohio State University, Columbus, OH 43210, USA
Chunbin Zhang - Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA
Lei Yin - Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
Deyu Fang - Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Sung Hong Back - School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea
Randal J Kaufman - Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Ling Yang - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. kzhang@med.wayne.edu jiemei.wang@wayne.edu ling-yang@uiowa.edu
Kezhong Zhang - Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA
Resource Type: Journal article
Publication Details: Science signaling, Vol.11(530), p.eaao4617
Publisher: United States
DOI: 10.1126/scisignal.aao4617
PMID: 29764990
PMCID: PMC6075656
ISSN: 1945-0877
eISSN: 1937-9145
Grant note: R01 DK109036 / NIDDK NIH HHS P30 DK020572 / NIDDK NIH HHS R01 DK103185 / NIDDK NIH HHS R01 DK042394 / NIDDK NIH HHS R37 DK042394 / NIDDK NIH HHS R01 DK090313 / NIDDK NIH HHS R01 DK108835 / NIDDK NIH HHS R01 AR066634 / NIAMS NIH HHS R01 CA198103 / NCI NIH HHS R21 ES017829 / NIEHS NIH HHS
Language: English
Date published: 05/15/2018
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology
Record Identifier: 9984025477602771

Metrics

41 Record Views

83 Times Cited - Web of Science

See more details