Pakl mediates the stimulatory effect of insulin and curcumin on hepatic ChREBP expression

• Published in: 分子细胞生物学报：英文版 Vol. 9; no. 5; pp. 384 - 394
• Main Author: Kejing Zeng;Lili Tian;Adam Sirek;Weijuan Shao;Ling Liu;Yu-Ting Chiang;Jonathan Chernoff;Dominic S. Ng;Jianping Weng;Tianru Jin
• Format: Journal Article
• Language: English
• Published: 2017
• ISSN: 1674-2788

Insulin can stimulate hepatic expression of carbohydrate-responsive element-binding protein （ChREBP）. As recent studies revealed potential metabolic beneficial effects of ChREBP, we asked whether its expression can also be regulated by the dietary polyphenoi curcumin. We also aimed to determine mechanisms underlying ChREBP stimulation by insulin and curcumin. The effect of insulin on ChREBP expression was assessed in mouse hepatocytes, while the effect of curcumin was assessed in mouse hepatocytes and with curcumin garage in mice. Chemical inhibitors for insulin signaling molecules were utilized to identify involved signaling molecules, and the involvement of p21-activated protein kinase 1 （Pakl） was determined with its chemical inhibitor and Pokl-/- hepatocytes. We found that both insulin and curcumin-stimulated ChREBP expression in Akt-independent but MEK/ERK-dependent manner, involving the inactivation of the transcriptional repressor Oct-1. Aged Pokl-/- mice showed reduced body fat volume. Pakl inhibition or its genetic deletion attenuated the stimulatory effect of insulin or curcumin on ChREBP expression. Our study hence suggests the existence of a novel signaling cascade Pakl/MEK/ERK/Oct-1 for both insulin and curcumin in exerting their glucose-lowering effect via promoting hepatic ChREBP production, supports the recognition of beneficial functions of ChREBP, and brings us a new overview on dietary polyphenols.