Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor

Xiao Cheng; Vijaya Bhaskar Baki; Matthew Moran; Baolong Liu; Jiujiu Yu; Miaoyun Zhao; Qingsheng Li; Jean-Jack Riethoven; Channabasavaiah B. Gurumurth; Edward N. Harris; Xinghui Sun

Molecular Metabolism (Aug 2024)

Liver matrin-3 protects mice against hepatic steatosis and stress response via constitutive androstane receptor

Xiao Cheng,
Vijaya Bhaskar Baki,
Matthew Moran,
Baolong Liu,
Jiujiu Yu,
Miaoyun Zhao,
Qingsheng Li,
Jean-Jack Riethoven,
Channabasavaiah B. Gurumurth,
Edward N. Harris,
Xinghui Sun

Affiliations

Xiao Cheng: Department of Biochemistry, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
Vijaya Bhaskar Baki: Department of Biochemistry, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
Matthew Moran: Department of Biochemistry, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA
Baolong Liu: Department of Nutrition and Health Sciences, University of Nebraska – Lincoln, 230 Filley Hall, Lincoln, NE 68583-0922, USA
Jiujiu Yu: Department of Nutrition and Health Sciences, University of Nebraska – Lincoln, 230 Filley Hall, Lincoln, NE 68583-0922, USA
Miaoyun Zhao: Nebraska Center for Virology, School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA
Qingsheng Li: Nebraska Center for Virology, School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, NE, USA
Jean-Jack Riethoven: Nebraska Center for Biotechnology, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA; Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska – Lincoln, Lincoln, NE 68588, USA
Channabasavaiah B. Gurumurth: Mouse Genome Engineering Core Facility, University of Nebraska Medical Center, Omaha, USA
Edward N. Harris: Department of Biochemistry, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA; Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska – Lincoln, Lincoln, NE 68588, USA; Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska – Lincoln, USA
Xinghui Sun: Department of Biochemistry, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA; Nebraska Center for Integrated Biomolecular Communication (NCIBC), University of Nebraska – Lincoln, Lincoln, NE 68588, USA; Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska – Lincoln, USA; Corresponding author. Department of Biochemistry, University of Nebraska – Lincoln, Beadle Center, 1901 Vine St, Lincoln, NE 68588, USA.

Journal volume & issue: Vol. 86
p. 101977

Abstract

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Objective: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise with the increasing obesity epidemic. Rezdiffra as an activator of a thyroid hormone receptor-beta is the only Food and Drug Administration approved therapy. As such, there is a critical need to improve our understanding of gene expression regulation and signaling transduction in MASLD to develop new therapies. Matrin-3 is a DNA- and RNA-binding protein involved in the pathogenesis of human diseases. Here we examined its previously uncharacterized role in limiting hepatic steatosis and stress response via the constitutive androstane receptor (CAR). Methods: Matrin-3 floxed and liver-specific knockout mice were fed either a chow diet or 60 kcal% high-fat diet (HFD) for up to 16 weeks. The mice were euthanized for different analysis including liver histology, lipid levels, and gene expression. Bulk RNA-seq, bulk ATAC-seq, and single-nucleus Multiome were used to examine changes of transcriptome and chromatin accessibility in the liver. Integrative bioinformatics analysis of our data and publicly available datasets and different biochemical assays were performed to identify underlying the molecular mechanisms mediating matrin-3's effects. Liver-tropic adeno-associated virus was used to restore the expression of CAR for lipid, acute phase genes, and histological analysis. Results: Matrin-3 expression is induced in the steatotic livers of mice. Liver-specific matrin-3 deletion exacerbated HFD-induced steatosis, acute phase response, and inflammation in the liver of female mice. The transcriptome and chromatin accessibility were re-programmed in the liver of these mice with signatures indicating that CAR signaling is dysregulated. Mechanistically, matrin-3 interacts with CAR mRNA, and matrin-3 deficiency promotes CAR mRNA degradation. Consequently, matrin-3 deletion impaired CAR signaling by reducing CAR expression. Matrin-3 levels positively correlate with CAR expression in human livers. Ces2a and Il1r1 were identified as new target genes of CAR. Interestingly, we found that CAR discords with the expression of its target genes including Cyp2b10 and Ces2a in response to HFD, indicating CAR signaling is dysregulated by HFD despite increased CAR expression. Dysregulated CAR signaling upon matrin-3 deficiency reduced Ces2a and de-repressed Il1r1 expression. CAR restoration partially abrogated the dysregulated gene expression, exacerbated hepatic steatosis, acute phase response, and inflammation in liver-specific matrin-3 knockout mice fed a HFD. Conclusions: Our findings demonstrate that matrin-3 is a key upstream regulator maintaining CAR signaling upon metabolic stress, and the matrin-3-CAR axis limits hepatic steatosis and stress response signaling that may give insights for therapeutic intervention.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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