Chen L, Liu Q, Tang Q, Kuang J, Li H, Pu S, Wu T, Yang X, Li R, Zhang J, Zhang Z, Huang Y, Li Y, Zou M, Jiang W, Li T, Gong M, Zhang L, Wang H, Qu A, Xie W, He J. Hepatocyte-specific Sirt6 deficiency impairs ketogenesis. J Biol Chem 2018 Dec 10 [Epub ahead of print] PMID: 30530497.
ABSTRACT
Sirt6 is nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase with a critical role of 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 fat-specific induction of protein 27 (Fsp27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27β expression by interacting with cyclic-AMP response-element binding protein H (Crebh) and preventing its recruitment to the Fsp27β 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.
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