SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1.

Abstract

Fatty liver disease is the most prevalent chronic liver disorder, which is manifested by hepatic triglyceride elevation, inflammation, and fibrosis. Sirtuin 6 (Sirt6), an NAD+-dependent deacetylase, has been implicated in hepatic glucose and lipid metabolism; however, the underlying mechanisms are incompletely understood. The aim of this study was to identify and characterize novel players and mechanisms that are responsible for the Sirt6-mediated metabolic regulation in the liver. We generated and characterized Sirt6 liver-specific knockout mice regarding its role in the development of fatty liver disease. We used cell models to validate the molecular alterations observed in the animal models. Biochemical and molecular biological approaches were used to illustrate protein-protein interactions and gene regulation. Our data show that Sirt6 liver-specific knockout mice develop more severe fatty liver disease than wild-type mice do on a Western diet. Hepatic Sirt6 deficiency leads to elevated levels and transcriptional activities of carbohydrate response element binding protein (ChREBP) and sterol regulatory element binding protein 1 (SREBP1). Mechanistically, our data reveal protein-protein interactions between Sirt6 and liver X receptor α (LXRα), ChREBP, or SREBP1c in hepatocytes. Moreover, Sirt6 suppresses transcriptional activities of LXRα, ChREBP, and SREBP1c through direct deacetylation. In conclusion, this work has identified a key mechanism that is responsible for the salutary function of Sirt6 in the inhibition of hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1.

• Authors: Chaoyu Zhu, Menghao Huang, Hyeong-Geug Kim, Kushan Chowdhury, Jing Gao, Sheng Liu, Jun Wan, Li Wei, X Charlie Dong
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1867 Issue 12 Pg. 166249 (12 01 2021) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 34425214 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Liver X Receptors
• MLXIPL protein, human
• Sterol Regulatory Element Binding Protein 1
• Triglycerides
• Sirt6 protein, mouse
• SIRT6 protein, human
• Sirtuins
• Glucose

Topics

• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics)
• Diet, Western
• Fatty Liver (genetics, pathology)
• Glucose (metabolism)
• Hepatocytes (metabolism)
• Humans
• Lipid Metabolism (genetics)
• Lipogenesis (genetics)
• Liver (metabolism)
• Liver X Receptors (genetics)
• Mice, Knockout
• Phagocytosis (genetics)
• Sirtuins (genetics)
• Sterol Regulatory Element Binding Protein 1 (genetics)
• Triglycerides (blood)
• Mice