Nutrient-driven histone acetylation underlies energy storage and mobilization

Area of Science:

• Metabolic regulation
• Epigenetics
• Molecular biology

Background:

• Energy storage and mobilization maintain metabolic homeostasis.
• Imbalances cause metabolic dysfunction, but the link to epigenetics is unclear.
• Understanding epigenetic control of energy balance is crucial.

Purpose of the Study:

• Investigate the epigenetic mechanisms linking metabolic status to energy storage and mobilization.
• Clarify the roles of glucose, ketone bodies, ACSS2, and BRD4 in this process.
• Explore therapeutic potential for metabolic diseases.

Main Methods:

• Studied epigenetic modifications (histone acetylation) in overfeeding and fasting states.
• Assessed the involvement of acyl-CoA short-chain synthetase 2 (ACSS2) and BRD4.
• Utilized mouse models with high-fat, ketogenic, and fasting diets.
• Examined effects of BRD4 inhibition on non-alcoholic fatty liver disease (NAFLD) and hepatic steatosis.

Main Results:

• Increased glucose in overfeeding enhances histone acetylation via ACSS2, promoting lipogenesis.
• Ketone bodies in fasting alter histone acetylation and gene expression, shifting to catabolism (fatty acid oxidation).
• BRD4 is essential for recognizing histone acetylation and regulating transcription in both states.
• BRD4 inhibition ameliorates high-fat diet-induced NAFLD but worsens hepatic steatosis in fasting/ketogenic states.

Conclusions:

• Epigenetic regulation of energy storage/mobilization is tied to glucose and ketone body availability.
• BRD4 plays a context-dependent role in metabolic adaptation.
• Targeting ACSS2 pathways may offer new treatments for metabolic diseases like NAFLD.