Abstract
Aberrant gluconeogenic gene expression is associated with diabetes, glycogen storage disease, and liver cancer. However, little is known how these genes are regulated at the chromatin level. In this study, we investigated in HepG2 cells whether histone demethylation is a potential mechanism. We found that knockdown or pharmacological inhibition of histone demethylase LSD1 causes remarkable transcription activation of two gluconeogenic genes, FBP1 and G6Pase, and consequently leads to increased de novo glucose synthesis and decreased intracellular glycogen content. Mechanistically, LSD1 occupies the promoters of FBP1 and G6Pase, and modulates their H3K4 dimethylation levels. Thus, our work identifies an epigenetic pathway directly governing gluconeogenic gene expression, which might have important implications in metabolic physiology and diseases.
Highlights
Hepatic glucose production is essential for maintaining blood glucose homeostasis, which ensures a steady fuel supply for many cell types in the body
While gluconeogenesis runs in the opposite direction of glycolysis and shares several reverse enzymatic reactions with glycolysis, three steps, catalyzed by a separate set of key enzymes, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBP1) and glucose 6phosphatase (G6Pase), are non-reversible and largely determine the rate of gluconeogenesis
We recently showed that histone demethylase Jhdm1a indirectly suppresses the expression of PEPCK and G6Pase through demethylation of H3 lysine 36 (H3K36) at the C/EBPa locus [20]
Summary
Hepatic glucose production is essential for maintaining blood glucose homeostasis, which ensures a steady fuel supply for many cell types in the body. Hepatic glucose production is accomplished by two processes, initially via glycogenolysis that breaks down glycogen in the first few hours after a meal, and subsequently via gluconeogenesis that de novo synthesizes glucose from noncarbohydrate precursors during prolonged fasting. Uncontrolled gluconeogenesis is a major contributor to hyperglycemia in both type 1 and type 2 diabetes [1,2,3]. While gluconeogenesis runs in the opposite direction of glycolysis and shares several reverse enzymatic reactions with glycolysis, three steps, catalyzed by a separate set of key enzymes, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBP1) and glucose 6phosphatase (G6Pase), are non-reversible and largely determine the rate of gluconeogenesis. G6Pase catalyzes the terminal step in the glycogenolytic pathway. Deficiency in G6Pase in patients results in glycogen storage disease Ia (GSD Ia), exhibiting hypoglycemia and abnormal hepatic accumulation of glycogen [4]
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