14-3-3 beta and gamma differentially regulate peroxisome proliferator activated receptor gamma(2) transactivation and hepatic lipid metabolism

Abstract

Peroxisome proliferator activated receptor (PPAR) gamma(2) plays important roles in glucose and lipid metabolism in hepatocytes. PPAR gamma(2) is involved in metabolic disorders, including obesity, diabetes, and fatty liver disease. Although the 14-3-3 proteins participate in a variety of cell signal pathways, the roles of the 14-3-3 proteins in regulating PPAR gamma(2) transactivation and hepatic lipid metabolism are unknown. We identified 14-3-3 beta and gamma as PPAR gamma(2) transcriptional regulators. We found that 14-3-3 beta and gamma competitively interacted with the phosphorylated Ser273 of PPAR gamma(2), which is important for regulating glucose and lipid metabolism. 14-3-3 beta increased the transcriptional activity of PPAR gamma(2) and enhanced the expression levels of PPAR gamma(2) target genes involved in lipogenesis and lipid transport In contrast, 14-3-3 gamma decreased PPAR gamma(2) transactivation and reduced the expression levels of PPAR gamma(2) target genes. A high concentration of free fatty acids increased PPAR gamma(2) expression and lipid accumulation. 14-3-3 beta enhanced hepatic lipogenesis, which is a major symptom of non-alcoholic fatty liver disease. However, 14-3-3 gamma suppressed hepatic lipid accumulation in the presence of high free fatty acids. These findings indicate that 14-3-3 beta and gamma are novel PPAR gamma(2) regulators and are involved in hepatic lipid metabolism. 14-3-3 beta and gamma can be therapeutic target molecules to treat non-alcoholic fatty liver disease. (C) 2015 Elsevier B.V. All rights reserved.