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Hepatocyte-specific Sirt6 deficiency impairs ketogenesis.
- Source :
-
Journal of Biological Chemistry . 2/1/2019, Vol. 294 Issue 5, p1579-1589. 11p. - Publication Year :
- 2019
-
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 (fatspecific 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 Fsp27βgene 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *DEACETYLASES
*ENZYMES
*SIRTUINS
*LIPIDS
*BIOMOLECULES
*LIPID metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 294
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Biological Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 134420664
- Full Text :
- https://doi.org/10.1074/jbc.RA118.005309