| Autor: |
Kyle D. Copps, Rongya Tao |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Gastroenterology |
| ISSN: |
0016-5085 |
| DOI: |
10.1053/j.gastro.2022.04.044 |
| Popis: |
BACKGROUND AND 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 (ATD) 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 versus 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 over-expression or activation enhances autophagic ATZ degradation. CONCLUSION: 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 ATD liver disease therapies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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