期刊
GASTROENTEROLOGY
卷 163, 期 1, 页码 270-284出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2022.03.010
关键词
Liver Disease; Liver Fibrosis; Proteostasis; Autophagy; Oxidative Phosphorylation.
资金
- National Institutes of Health (NIH) [PO1DK096990, RO1DK131215]
- Children's Discovery Institute of Washington University
- St Louis Children's Hospital
- Washington University School of Medicine (WUSM) Department of Pediatrics
- National Cancer Institute Cancer Center Support grant [P30 CA091842]
- NIH's National Center for Advancing Translational Sciences Clinical and Translational Science Award program grant [UL1 TR002345.]
- NIH Shared Instrumentation grant [S10 RR027552]
- WUSM Digestive Disease Research Core Center [P30-DK52574]
- [RO1 DK11757]
Insulin signaling exacerbates hepatic proteotoxicity in PiZ mice with alpha 1-antitrypsin deficiency, and PGC1 alpha is identified as a novel therapeutic target.
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 alpha 1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded alpha 1-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-gamma-coactivator-1 alpha (PGC1 alpha) expression in PiZ-LIRKO mice. Because PGC1 alpha 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 PGC1 alpha overexpression or activation enhances autophagic ATZ degradation. CONCLUSIONS: These data implicate suppression of autophagic ATZ degradation by down-regulation of PGC1 alpha as one mechanism by which insulin signaling exacerbates hepatic proteotoxicity in PiZ mice, and identify PGC1 alpha as a novel target for development of new human alpha 1-antitrypsin deficiency liver disease therapies.
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