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Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration
Zheng Sun1, Russell A Miller, Rajesh T Patel
1Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Nature Medicine
|May 8, 2012
Summary
Depleting histone deacetylase 3 (Hdac3) in the liver improves insulin sensitivity and glucose tolerance in mice with fatty liver disease. This occurs by rerouting metabolism and increasing lipid storage in lipid droplets.
Area of Science:
- Metabolic disease research
- Epigenetics and circadian biology
- Hepatology
Background:
- Fatty liver disease is linked to obesity and type 2 diabetes.
- Hepatic lipid accumulation can worsen insulin resistance.
- Histone deacetylase 3 (Hdac3) regulates the daily rhythm of liver fat production.
Purpose of the Study:
- To investigate the role of Hdac3 in hepatic lipid metabolism and insulin sensitivity.
- To determine the effects of liver-specific Hdac3 depletion on metabolic health.
Main Methods:
- Liver-specific depletion of Hdac3 in mice.
- Assessment of insulin sensitivity and glucose tolerance.
- Analysis of hepatic lipid metabolism and gene expression.
Main Results:
- Hdac3 depletion led to severe fatty liver (steatosis) but increased insulin sensitivity and glucose tolerance.
- Metabolic pathways were rerouted towards lipid synthesis and storage.
- Perilipin 2, a lipid droplet protein, was induced and contributed to steatosis and improved glucose tolerance.
Conclusions:
- Sequestration of hepatic lipids in perilipin 2-coated droplets ameliorates insulin resistance.
- Hdac3 is a key epigenetic regulator linking circadian rhythms to liver metabolism.
- Targeting Hdac3 may offer therapeutic strategies for fatty liver disease and related metabolic disorders.
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