SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα

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