李于：sirt1 Regulation of Energy Metabolism: Attenuation of Hepatic Steatosis and Obesity

Fibroblast growth factor 21 (FGF21) is the hepatocyte-derived hormone that regulates fatty acid metabolism and has potential to treat obesity and diabetes. We recently indicate that hepatic overexpression of sirt1 in diabetic mice attenuates hepatic steatosis and insulin resistance. However, the in vivo long-term consequence of hepatic sirt1 ablation in liver physiology remains unknown.

We showed that hepatocyte-specific sirt1 knockout (sirt1 LKO) mice with the albumin Cre-loxP system exhibited a striking phenotype with greater propensity for obesity on a chow diet, characterized by increased whole body mass and fat mass, reduced energy expenditure, and unaltered food intake and physical activity. The obese phenotypes of sirt1 LKO mice were associated with reduced hepatic and circulating levels of fasting FGF21.

Hepatic impairment of FGF21 repressed expression of key enzymes involving fatty acid oxidation such as CPT1α and MCAD, and inhibited expression of ketogenic enzymes including ACAT1, HMGCS2, HMGCL, and BDH1, thereby reducing plasma β–hydroxybutyrate levels in sirt1 LKO mice. Moreover, transcriptional activity of a FGF21 promoter-driven luciferase reporter was stimulated by sirt1 activators, resveratrol and SRT1720, in sirt1+/+ MEFs, but not in sirt1-/- MEFs.

The ability of resveratrol and SRT1720 to stimulate FGF21 protein was abolished by sirt1 H335A inactive mutant or by nicotinamide and splitomicin in HepG2 cells. Induction of FGF21 by sirt1 activators enhanced expression of key enzymes for fatty acid oxidation and ketogenesis.

These in vivo and in vitro findings characterize 1) hepatic sirt1 as a master regulator of FGF21; 2) sirt1-dependent activation of FGF21 in liver as a component for adaptive fasting response; and 3) defective hepatic sirt1 and FGF21 signaling as a key pathological determinant of energy metabolic abnormality and obesity susceptibility.