SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPAR?.

ABSTRACT: The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPAR? signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPAR? and its response element within promoter regions and activates gene transcription. Sirt6+/- results in significantly reduced PPAR?-induced ?-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 ?-oxidation genes in a PPAR?-dependent manner. Furthermore, SIRT6 mediates PPAR? inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPAR? coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPAR? 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.

SUBMITTER: Naiman S 

PROVIDER: S-EPMC7165364 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature