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

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.

Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

“…Animals were treated with twice-daily subcutaneous injections until the end of the experiment. Rats with repeated insulin injections have not shown any hypoglycemic episodes (Poretsky et al 1992, Bogovich et al 1999, Damario et al 2000, Zhang et al 2018. Detailed analysis of endocrine and metabolic parameters as well as the uterine morphology in these animals has been reported previously (Zhang et al 2016).…”

“…Experiment 1: Rats were randomly divided into control (saline treatment, n = 20) and experimental (PCOSlike, n = 20) groups. The experimental group was treated with insulin plus hCG to induce a PCOS-like metabolic and reproductive phenotype, and the control rats were treated with an equal volume of saline (Zhang et al 2016(Zhang et al , 2018. In brief, insulin was started at 0.5 IU/day and gradually increased to 6.0 IU/day between day 1 and the day 22 to induce hyperinsulinemia and insulin resistance, and 3.0 IU/day hCG was given on all 22 days to induce hyperandrogenism.…”

Circulating levels of C1q/TNF‐α‐related protein 6 (CTRP6) in polycystic ovary syndrome

“…The resulting pathologic state mimics metabolic syndrome, and is associated with a number of disorders: impaired glucose tolerance, type II diabetes mellitus (T2DM), dyslipidemia, obesity, hypertension, and cardiovascular disease . In fact, insulin resistance accompanied by a degree of adiposity, and hyperandrogenism resulting from an elevated biosynthesis of androgens by theca cells, create a bidirectional link, both of which aggravate the chronic state of low‐grade inflammation in PCOS . Twenty‐two percent of these patients concomitantly suffer from recurrent pregnancy loss (RPL) with an exaggerated inflammatory response at the feto–maternal interface .…”

Circulating levels of Meteorin-like protein in polycystic ovary syndrome: A case-control study

“…Females affected by PCOS may suffer from fertility challenges, oblivious to their ovulatory disorder until they become diagnosed with habitual abortion, also known as recurrent pregnancy loss (RPL)-defined as at least two consecutive abortions within the first 20 weeks of pregnancy, with an incidence of 1in 300 pregnancies [10]. The pathogenesis of PCOS shares several features with metabolic syndrome (MetS), including dysfunctional adipose tissue with visceral adiposity, impaired insulin action with an increased risk for developing type II diabetes mellitus (T2DM), proatherogenic dyslipidemia, non-alcoholic fatty liver disease (NAFLD), and metaflammation [11][12][13][14].…”