Amino Acid Deprivation Increases Lipid Accumulation in HepG2 Hepatoma Cells through Repression of Histone Deacetylase 3 (HDAC3)

Abstract

Hepatic lipid overload is considered a predisposition for the development of fatty liver disease. Amino acid deprivation has been linked to lipogenesis in mouse liver. The present study investigated mechanisms of amino acid deprivation on hepatic lipid accumulation. Knockout of histone deacetylase HDAC3 in mice leads to genome‐wide histone hyperacetylation and increased expressions of lipogenic genes in mouse liver. Amino acid deprivation was induced by incubating HepG2 human hepatoma cells with amino acid‐free media. mRNA expression of Hdac3 was decreased significantly by 4 h amino acid deprivation. This is correlated with a significant increase in lipid accumulation in the cells using Oil red O and immunofluorescence staining of BODIPY. The lipid accumulation was accompanied with an increased mRNA expression of lipogenic genes including Srebf1 and Fasn in HepG2 cells. To confirm the involvement of HDAC3 in the amino acid deprivation‐induced lipid accumulation, HDAC3 was overexpressed in HepG2 cells and the overexpression abolished lipid accumulation by amino acid deprivation. Knockdown of HDAC3 induced mRNA expressions of Srebf1 and Fasn in HepG2 cells, leading to lipid accumulation. Therefore amino acid deprivation caused reduction of HDAC3, leading to the increased expression of lipogenic genes and lipid accumulation in HepG2 cells.