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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is an asymptomatic chronic liver disease, and it is thought to affect 25%–45% of the adult population worldwide and is recognized as the leading cause of liver dysfunction in Western societies [1]
Because a more pronounced hepatic steatosis, inflammatory responses, and hepatocyte cell damage were observed in insulin+human chorionic gonadotropin (hCG)-induced polycystic ovary syndrome (PCOS)-like rats, our finding suggest that nonalcoholic fatty liver disease (NAFLD) seen in PCOS patients is dependent of hyperandrogenism and insulin resistance
We report for the first time that hyperinsulinemia, hyperandrogenism, and a combination of hyperandrogenism and insulin resistance all contribute to development of hepatic steatosis as a result of impairment of lipid metabolism in the female rat liver
Summary
Nonalcoholic fatty liver disease (NAFLD) is an asymptomatic chronic liver disease, and it is thought to affect 25%–45% of the adult population worldwide and is recognized as the leading cause of liver dysfunction in Western societies [1]. NAFLD-induced hepatocellular injury presents a wide clinical spectrum ranging from simple steatosis to nonalcoholic steatohepatitis and cirrhosis [2,3]. Recent studies indicate that women with polycystic ovary syndrome (PCOS) have an increased prevalence of NAFLD [4,5]. One important goal of research is to identify novel and specific biomarkers, which can be used for accurate prediction of and treatment with NAFLD in PCOS patients. This has been hampered by a lack of understanding of the mechanisms underlying the development of hepatic steatosis and aberrant inflammatory responses in the female liver
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