4-Phenylbutyric Acid Increases GLUT4 Gene Expression through Suppression of HDAC5 but not Endoplasmic Reticulum Stress

• Main Authors: Hailong Hu, Li Li, Changlin Wang, Hongjuan He, Ke Mao, Xiao Ma, Ruoyu Shi, Yuri Oh, FengWei Zhang, Ying Lu, Qiong Wu, Ning Gu
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2014-06-01
• Series: Cellular Physiology and Biochemistry
• Subjects: 4-PBA; GLUT4; HDAC5; ER stress
• Online Access: http://www.karger.com/Article/FullText/362967
• ISSN: 1015-8987; 1421-9778

Background: The chemical chaperone 4-phenylbutyric acid (4-PBA) has been shown to relieve endoplasmic reticulum (ER) stress. Therefore, it improves insulin sensitivity and promotes glucose metabolism in skeletal muscle. Glucose transporter type 4 (GLUT4), as a major glucose transporter protein, plays a central role in glucose metabolism. Until now, it has been unclear whether 4-PBA affects GLUT4 gene expression and thus, contributes to glucose metabolism. Methods: C2C12 myotubes were treated with 4-PBA, tunicamycin or butyrate and subjected to Western blot and RT-PCR. Results: 4-PBA-treated C2C12 myotubes increased GLUT4 expression and promoted glucose metabolism. Most interestingly, GLUT4 gene expression induced by 4-PBA was not associated with ER stress even in the presence of tunicamycin, an ER stress inducer. Moreover, we also found that 4-PBA inhibited histonedeacetylase 5 (HDAC5) expression in C2C12 myotubes, resulting in hyperacetylation of the histone H3 at the myocyte enhancer factor 2 (MEF2) binding site. This increased the binding of MEF2A to the site on the GLUT4 promoter, resulting in increased GLUT4 expression. Conclusions: Our data indicate that 4-PBA increases GLUT4 expression by acetylating the MEF2 site to increase the MEF2A binding through a mechanism that involves suppression of the HDAC5 pathway, but without involving ER stress.