Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis

Canghai Guan; Xinlei Zou; Chengru Yang; Wujiang Shi; Jianjun Gao; Yifei Ge; Zhaoqiang Xu; Shaowu Bi; Xiangyu Zhong

Molecular Metabolism (Nov 2024)

Polyribonucleotide nucleotidyltransferase 1 participates in metabolic-associated fatty liver disease pathogenesis by affecting lipid metabolism and mitochondrial homeostasis

Canghai Guan,
Xinlei Zou,
Chengru Yang,
Wujiang Shi,
Jianjun Gao,
Yifei Ge,
Zhaoqiang Xu,
Shaowu Bi,
Xiangyu Zhong

Affiliations

Canghai Guan: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, 148 Baojian Street, Harbin 150086, Heilongjiang, China
Xinlei Zou: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Chengru Yang: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Wujiang Shi: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Jianjun Gao: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Yifei Ge: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Zhaoqiang Xu: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Shaowu Bi: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China
Xiangyu Zhong: General Surgery Department, The 2nd Affiliated Hospital of Harbin Medical University, 148 Baojian Street, Harbin 150086, Heilongjiang Province, China; Corresponding author.

Journal volume & issue: Vol. 89
p. 102022

Abstract

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Objective: Metabolic-associated fatty liver disease (MAFLD) represents one of the most prevalent chronic liver conditions worldwide, but its precise pathogenesis remains unclear. This research endeavors to elucidate the involvement and molecular mechanisms of polyribonucleotide nucleotidyltransferase 1 (PNPT1) in the progression of MAFLD. Methods: The study employed western blot and qRT-PCR to evaluate PNPT1 levels in liver specimens from individuals diagnosed with MAFLD and in mouse models subjected to a high-fat diet. Cellular studies investigated the effects of PNPT1 on lipid metabolism, apoptosis, and mitochondrial stability in hepatocytes. Immunofluorescence was utilized to track the subcellular movement of PNPT1 under high lipid conditions. RNA immunoprecipitation and functional assays were conducted to identify interactions between PNPT1 and Mcl-1 mRNA. The role of PPARα as an upstream transcriptional regulator of PNPT1 was investigated. Recombinant adenoviral vectors were utilized to modulate PNPT1 expression in vivo. Results: PNPT1 was found to be markedly reduced in liver tissues from MAFLD patients and HFD mice. In vitro, PNPT1 directly regulated hepatic lipid metabolism, apoptosis, and mitochondrial stability. Under conditions of elevated lipids, PNPT1 relocated from mitochondria to cytoplasm, modifying its physiological functions. RNA immunoprecipitation revealed that the KH and S1 domains of PNPT1 bind to and degrade Mcl-1 mRNA, which in turn affects mitochondrial permeability. The transcriptional regulator PPARα was identified as a significant influencer of PNPT1, impacting both its expression and subsequent cellular functions. Alterations in PNPT1 expression were directly correlated with the progression of MAFLD in mice. Conclusions: The study confirms the pivotal function of PNPT1 in the development of MAFLD through its interactions with Mcl-1 and its regulatory effects on lipid metabolism and mitochondrial stability. These insights highlight the intricate association between PNPT1 and MAFLD, shedding light on its molecular pathways and presenting a potential new therapeutic avenue for MAFLD management.

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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