Oncotarget

Research Papers:

Hyperandrogenism and insulin resistance contribute to hepatic steatosis and inflammation in female rat liver

Yuehui Zhang _, Fanci Meng, Xiaoyan Sun, Xue Sun, Min Hu, Peng Cui, Edvin Vestin, Xin Li, Wei Li, Xiao-Ke Wu, John-Olov Jansson, Linus R. Shao and Håkan Billig

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Oncotarget. 2018; 9:18180-18197. https://doi.org/10.18632/oncotarget.24477

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Abstract

Yuehui Zhang1,2, Fanci Meng1, Xiaoyan Sun1, Xue Sun1, Min Hu2, Peng Cui2,3,4, Edvin Vestin2, Xin Li2,5,6, Wei Li1, Xiao-Ke Wu1, John-Olov Jansson2, Linus R. Shao2 and Håkan Billig2

1Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China

2Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden

3Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College and Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Institute of Brain Science, Fudan University, 200032 Shanghai, China

4Institute of Integrative Medicine of Fudan University, 200032 Shanghai, China

5Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China

6Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China

Correspondence to:

Yuehui Zhang, email: [email protected]

Linus R. Shao, email: [email protected]

Keywords: PCOS; hyperandrogenism; insulin resistance; hepatic metabolism; inflammation

Received: November 21, 2017     Accepted: January 25, 2018     Epub: February 09, 2018     Published: April 06, 2018

ABSTRACT

Women with polycystic ovary syndrome (PCOS) are at high risk for nonalcoholic fatty liver disease (NAFLD). While insulin resistance is a common trait for both PCOS and NAFLD, hyperandrogenism is also considered to be a key factor contributing to PCOS, and the molecular mechanisms behind the interactions between insulin resistance and hyperandrogenism in the female liver remain largely unexplored. Using chronic treatment with insulin and/or human chorionic gonadotropin (hCG), we showed that all female rats with different treatments induced imbalance between de novo lipogenesis and mitochondrial β-oxidation via the Pparα/β–Srebp1/2–Acc1 axis, resulting in varying degrees of hepatic steatosis. Given the fact that hepatic lipid metabolism and inflammation are tightly linked processes, we found that hCG-induced hyperandrogenic rats had strongly aggravated hepatic inflammation. Further mechanistic investigations revealed that dysregulation of the IRS–PI3K–Akt signaling axis that integrated aberrant inflammatory, apoptotic and autophagic responses in the liver was strongly associated with hyperandrogenism itself or combined with insulin resistance. Additionally, we found that hCG-treated and insulin+hCG-induced rats developed visceral adipose tissue inflammation characterized by the presence of “crown like” structure and increased inflammatory gene expression. Because a more pronounced hepatic steatosis, inflammatory responses, and hepatocyte cell damage were observed in insulin+hCG-induced PCOS-like rats, our finding suggest that NAFLD seen in PCOS patients is dependent of hyperandrogenism and insulin resistance.


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