SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα
| Autor: | Ifat Abramovich, Doron Gerber, Matthew D. Hirschey, Olga Ilkayeva, Yael Shahar, Asaf A. Gertler, Asael Roichman, Yair Glick, Noga Touitou, Haim Y. Cohen, Orly Yaron, Matan Y. Avivi, Liat Nahum, Robert A. Harris, Frank K. Huynh, Reuven Gil, Yariv Kanfi, Eyal Gottlieb, Shoshana Naiman, Batia Lerrer, Tirza Doniger |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pyruvate decarboxylation SIRT6 Male Response element Blotting Western Mice Transgenic General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice Nuclear Receptor Coactivator 2 0302 clinical medicine Gene expression Coactivator medicine Animals Humans Immunoprecipitation Sirtuins PPAR alpha Acetylcarnitine Beta oxidation lcsh:QH301-705.5 Cells Cultured Chemistry Acetylation Cell biology Metabolic pathway 030104 developmental biology HEK293 Cells Liver lcsh:Biology (General) Oxidation-Reduction 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cell Reports, Vol 29, Iss 12, Pp 4127-4143.e8 (2019) |
| ISSN: | 2211-1247 |
| Popis: | Summary: The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/− results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver. : How the pro-longevity enzyme SIRT6 coordinates between various metabolic pathways is still obscure. Here, Naiman et al. show that SIRT6 activates PPARα to promote fatty acid beta oxidation and inhibit pyruvate oxidation during fasting. This ultimately decides the energy source under nutrient-limited conditions, promoting fat usage over other energy sources. Keywords: SIRT6, PPARα, beta-oxidation, liver, deacetylase, fasting |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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