Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

Area of Science:

• Biochemistry
• Metabolic Disease Research
• Molecular Biology

Background:

• Sirtuin 6 (Sirt6), an NAD+-dependent deacetylase, is crucial for hepatic lipid metabolism.
• Ketogenesis, a key process in hepatic lipid metabolism, is regulated by complex signaling networks.
• The precise role of Sirt6 in regulating ketogenesis remains largely uncharacterized.

Purpose of the Study:

• To elucidate the function of Sirt6 in mediating ketogenesis.
• To investigate the molecular mechanisms by which Sirt6 influences hepatic lipid metabolism and inflammation.
• To explore the potential of Sirt6 as a therapeutic target for metabolic disorders.

Main Methods:

• Utilized hepatocyte-specific Sirt6 deficiency (HKO) mouse models fed a ketogenic diet (KD).
• Performed Sirt6 overexpression studies in primary mouse hepatocytes.
• Investigated the interaction between Sirt6, Crebh (cAMP response element-binding protein H), and Fsp27 (fat-specific induction of protein 27) gene expression.
• Analyzed hepatic steatosis, inflammation, and ketogenesis markers.

Main Results:

• Hepatocyte-specific Sirt6 deficiency in KD-fed mice impaired ketogenesis due to increased Fsp27 expression.
• Sirt6 overexpression in hepatocytes promoted ketogenesis.
• Sirt6 repressed Fsp27β expression by inhibiting Crebh recruitment to the Fsp27β promoter.
• KD-fed HKO mice exhibited exacerbated hepatic steatosis and inflammation.
• Fsp27 silencing ameliorated hypoketonemia and other metabolic dysfunctions in KD-fed HKO mice.

Conclusions:

• The Sirt6-Crebh-Fsp27 signaling axis is critical for regulating hepatic ketogenesis, lipid metabolism, and inflammation.
• Sirt6 plays a vital role in adapting to ketogenic diets by modulating ketogenesis.
• Targeting Sirt6 presents a potential therapeutic strategy for managing metabolic diseases associated with impaired ketogenesis and hepatic lipid dysregulation.