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Pak1 mediates the stimulatory effect of insulin and curcumin on hepatic ChREBP expression Free
Kejing Zeng1,†, Lili Tian2,†, Adam Sirek3, Weijuan Shao2, Ling Liu2, Yu-Ting Chiang3, Jonathan Chernoff4, Dominic S. Ng3,5, Jianping Weng1,*, and Tianru Jin2,3,*
1 Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-Sen University and Guangdong Provincial Key Laboratory of
Diabetology, Guangzhou 510630, China
2 Toronto General Research Institutes, University Health Network, Toronto M5G 1L7, Canada
3 Department of Physiology, Faculty of Medicine, University of Toronto, Toronto M5S 1A8, Canada
4 Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA
5 Keenan Research Centre, Li Ka Shing Knowledge Institute, Department of Medicine, St. Michael’s Hospital, Toronto M5B 1W8, Canada † These authors contributed equally to this work. *Correspondence to:Tianru Jin, E-mail: tianru.jin@utoronto.ca; Jianping Weng, E-mail: wengjp@vip.163.com
J Mol Cell Biol, Volume 9, Issue 5, October 2017, Pages 384-394  https://doi.org/10.1093/jmcb/mjx031
Keyword: Akt, ChREBP, curcumin, dietary polyphenol intervention, insulin, Oct-1, Pak1

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 polyphenol 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 gavage in mice. Chemical inhibitors for insulin signaling molecules were utilized to identify involved signaling molecules, and the involvement of p21-activated protein kinase 1 (Pak1) was determined with its chemical inhibitor and Pak1−/− 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 Pak1−/− mice showed reduced body fat volume. Pak1 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 Pak1/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.