Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z

Authors

David A Rudnick
Jiansheng Huang
Tunda Hidvegi
Andrew S Chu
Pamela Hale
Admire Munanairi
Dennis J Dietzen
Paul F Cliften
Eric Tycksen
Andrew J Lutkewitte
Brian N Finck
Stephen C Pak
Gary A Silverman
David H Perlmutter

Publication Date

7-1-2022

Journal

Gastroenterology

DOI

10.1053/j.gastro.2022.03.010

PMID

35301011

PMCID

PMC9232923

PubMedCentral® Posted Date

7-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Insulin, Liver, Liver Cirrhosis, Mammals, Mice, Mice, Transgenic, Mutation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Signal Transduction, alpha 1-Antitrypsin Deficiency, liver disease, liver fibrosis, proteostasis, autophagy, oxidative phosphorylation

Abstract

BACKGROUND & AIMS: Insulin signaling is known to regulate essential proteostasis mechanisms.

METHODS: The analyses here examined effects of insulin signaling in the PiZ mouse model of α1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded α1-antitrypsin Z variant (ATZ) causes liver fibrosis and cancer.

RESULTS: We first studied the effects of breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with hepatocyte-specific insulin-receptor gene disruption). The results showed decreased hepatic ATZ accumulation and liver fibrosis in PiZ x LIRKO vs PiZ mice, with reversal of those effects when we bred PiZ x LIRKO mice onto a FOXO1-deficient background. Increased intracellular degradation of ATZ mediated by autophagy was identified as the likely mechanism for diminished hepatic proteotoxicity in PiZ x LIRKO mice and the converse was responsible for enhanced toxicity in PiZ x LIRKO x FOXO1-KO animals. Transcriptomic studies showed major effects on oxidative phosphorylation and autophagy genes, and significant induction of peroxisome proliferator-activated-receptor-γ-coactivator-1α (PGC1α) expression in PiZ-LIRKO mice. Because PGC1α plays a key role in oxidative phosphorylation, we further investigated its effects on ATZ proteostasis in our ATZ-expressing mammalian cell model. The results showed PGC1α overexpression or activation enhances autophagic ATZ degradation.

CONCLUSIONS: These data implicate suppression of autophagic ATZ degradation by down-regulation of PGC1α as one mechanism by which insulin signaling exacerbates hepatic proteotoxicity in PiZ mice, and identify PGC1α as a novel target for development of new human α1-antitrypsin deficiency liver disease therapies.