| First Author | Chen L | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 5 | Pages | 1579-1589 |
| PubMed ID | 30530497 | Mgi Jnum | J:274744 |
| Mgi Id | MGI:6294537 | Doi | 10.1074/jbc.RA118.005309 |
| Citation | Chen L, et al. (2019) Hepatocyte-specific Sirt6 deficiency impairs ketogenesis. J Biol Chem 294(5):1579-1589 |
| abstractText | Sirt6 is an NADH (NAD(+))-dependent deacetylase with a critical role in hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced Fsp27 (fat-specific induction of protein 27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27beta expression by interacting with Crebh (cAMP response element-binding protein H) and preventing its recruitment to the Fsp27beta gene promoter. The KD-fed HKO mice also showed exacerbated hepatic steatosis and inflammation. Finally, Fsp27 silencing rescued hypoketonemia and other metabolic phenotypes in KD-fed HKO mice. Our data suggest that the Sirt6-Crebh-Fsp27 axis is pivotal for hepatic lipid metabolism and inflammation. Sirt6 may be a pharmacological target to remedy metabolic diseases. |
