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Free Radic Biol Med. 2018 Aug 20;124:122-134. doi: 10.1016/j.freeradbiomed.2018.06.003. Epub 2018 Jun 5.

Oleanolic acid attenuates PCBs-induced adiposity and insulin resistance via HNF1b-mediated regulation of redox and PPARγ signaling.

Author information

1
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
2
Department of Gastrointestinal Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
3
Department of Cardiology, Chengdu Military General Hospital, Chengdu 610083, Sichuan Province, China.
4
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: cx-hai@fmmu.edu.cn.
5
Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, School of Public Health, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: xinwang@fmmu.edu.cn.

Abstract

Polychlorinated biphenyls (PCBs) exposure is closely associated with obesity and diabetes. However, the mechanism of PCBs-induced adiposity and insulin resistance is not clear and the intervention is limited. We have found that oleanolic acid (OA) is a natural triterpenoid, possessing antioxidant and anti-diabetic activity, and hepatocyte nuclear factor 1b (HNF1b) is an important regulator of glucose and lipid metabolism. The present study aimed to investigate the effect of OA on Aroclor 1254-induced adiposity and insulin resistance and explore the possible involvement of HNF1b. We showed that OA significantly attenuated Aroclor 1254-induced insulin resistance and abnormal changes of glucose and lipid parameters. OA inhibited the increase of adipose weight and adipocyte size in Aroclor 1254-treated mice and repressed adipocyte differentiation in vitro. In addition, OA markedly inhibited Aroclor 1254-induced increase of ROS, oxidant products, NOX4 expression, decrease of SOD1, SOD2, GCLC, GCLM and Gpx1 expression, and increase of PPARγ signaling. Aroclor 1254 resulted in a decrease of HNF1b expression in adipose of mice and adipocytes, which was inhibited by OA. Upregulation of HNF1b blocked Aroclor 1254-induced oxidative stress, adipocyte differentiation and insulin resistance. Downregulation of HNF1b inhibited OA-induced protective effects against Aroclor 1254-associated oxidative stress, adipocyte differentiation and insulin resistance. The antioxidant Vitamin C reduced Aroclor 1254-induced ROS generation in vitro, but had no significant effect on HNF1b expression, oxidative stress and metabolic dysfunction in vivo. OA could inhibit PCBs mixture-induced oxidative injury and glucose/lipid metabolic dysfunction via HNF1b-mediated regulation of redox homeostasis. Our data suggest that HNF1b is a new on/off switch of redox homeostasis and OA-stimulated HNF1b-endogenous antioxidant activity is a potential option for the intervention of PCBs exposure-related adiposity and insulin resistance.

KEYWORDS:

Hepatocyte nuclear factor 1b; Metabolic dysfunction; Oleanolic acid; Oxidative stress; Polychlorinated biphenyls; Vitamin C

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