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Role of Mechanistic Target of Rapamycin and Autophagy in Alcohol-Induced Adipose Atrophy and Liver Injury
- Source :
- Am J Pathol
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Chronic alcohol consumption induces adipose tissue atrophy. However, the mechanisms for how alcohol induces lipodystrophy and its impact on liver steatosis and injury are not fully elucidated. Autophagy is a highly conserved lysosomal degradation pathway, which regulates cellular homeostasis. Mice with autophagy deficiency in adipose tissue have impaired adipogenesis. However, whether autophagy plays a role in alcohol-induced adipose atrophy and how altered adipocyte autophagy contributes to alcohol-induced liver injury remain unclear. To determine the role of adipose autophagy and mechanistic target of rapamycin (mTOR) in alcohol-induced adipose and liver pathogenesis, we generated adipocyte-specific Atg5 knockout (KO), adipocyte-specific mTOR KO, adipocyte-specific Raptor KO, and adipocyte-specific tuberous sclerosis complex 1 KO mice by crossing floxed mice with Adipoq-Cre. The KO mice and their matched wild-type mice were challenged with chronic-plus-binge alcohol mouse model. Chronic-plus-binge alcohol induced adipose atrophy with increased autophagy and decreased Akt/mTOR signaling in epididymal adipose tissue in wild-type mice. Adipocyte-specific Raptor KO mice experienced exacerbated alcohol-induced steatosis, but neither adipocyte-specific mTOR nor adipocyte-specific tuberous sclerosis complex 1 KO mice exhibited similar detrimental effects. Adipocyte-specific Atg5 KO mice had increased circulating levels of fibroblast growth factor 21 and adiponectin and were resistant to alcohol-induced adipose atrophy and liver injury. In conclusion, autophagy deficiency in adipose tissue leads to reduced sensitivity to alcohol-induced adipose atrophy, which ameliorates alcohol-induced liver injury in mice.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
FGF21
ATG5
Adipose tissue
Tuberous Sclerosis Complex 1 Protein
Article
Autophagy-Related Protein 5
Pathology and Forensic Medicine
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Atrophy
Adipocyte
Internal medicine
Autophagy
medicine
Animals
Mechanistic target of rapamycin
PI3K/AKT/mTOR pathway
Mice, Knockout
Ethanol
biology
business.industry
TOR Serine-Threonine Kinases
Regulatory-Associated Protein of mTOR
medicine.disease
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
Adipose Tissue
chemistry
Chemical and Drug Induced Liver Injury, Chronic
Anti-Infective Agents, Local
biology.protein
030211 gastroenterology & hepatology
business
Signal Transduction
Subjects
Details
- ISSN :
- 00029440
- Volume :
- 190
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi.dedup.....6bf2527f5ab65101fbcb98fcb38c5a6d