Hepatocyte-specific Sirt6 Deficiency Impairs Ketogenesis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2018 Dec 12

PMID 30530497

Citations 9

Authors

Lei Chen

Qinhui Liu

Qin Tang

Jiangying Kuang

Hong Li

Shiyun Pu

Tong Wu

Xuping Yang

Rui Li

Jinhang Zhang

Zijing Zhang

Ya Huang

Yanping Li

Min Zou

Wei Jiang

Tao Li

Meng Gong

Lu Zhang

Hua Wang

Aijuan Qu

Wen Xie

Jinhan He

Affiliations

Soon will be listed here.

Abstract

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 Fsp27β expression by interacting with Crebh (cAMP response element-binding protein H) 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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