期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2119824119
关键词
AMPK; fat oxidation; mitochondria; NAFLD; autophagy
资金
- Diabetes Canada [DI-5-17-5302-GS]
- Canadian Institutes of Health Research [201709FDN-CEBA-116200]
- Novo Nordisk Foundation [NNF21OC0070257]
- Tier 1 Canada Research Chair
- J. Bruce Duncan Chair in Metabolic Diseases
- Canadian Institutes of Health Research
- Ontario Graduate Scholarship (Queen Elizabeth II Graduate Scholarship in Science and Technology)
- Douglas C. Russell Memorial Scholarship
- Canadian Institutes of Health Research Postdoctoral fellowship
- Novo Nordisk Foundation Center for Basic Metabolic Research [NNF18CC0034900]
This study demonstrates the important physiological role of AMPK ss 1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis, and autophagy under conditions of high lipid availability.
Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK ss 1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPK ss 1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPK ss 1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.
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