Endocrine Abstracts

Accumulating clinical data suggest that women with polycystic ovary syndrome (PCOS) are at high risk for nonalcoholic fatty liver disease (NAFLD). However, it is not clear whether hyperinsulinemia and hyperandrogenism act concomitantly or independently to induce hepatic steatosis and inflammation, and the molecular mechanisms behind the interactions between insulin resistance and hyperandrogenism in the female liver remain largely unexplored. To achieve hyperinsulinemia, insulin resistance, and hyperandrogenism, we treated rats chronically with insulin, human chorionic gonadotropin (hCG), or a combination of insulin and hCG. We showed that the different treatments induced varying degrees of hepatic steatosis in rats. While hCG-treated rats had strongly aggravated hepatic inflammation, insulin+hCG-treated rats exhibited the hallmarks of metabolic alterations and hepatocyte cell damage. Further mechanistic study revealed that the expression of a number of genes (Srebp-1, Srebp-2, Gpam, Ppara, Pparg, Lxrα, E2f1, Il-6, Mcp1, Tgfb, and Ctgf) and proteins (AceCS1, p-ACL, IRβ, p110-PI3K, p-Akt (T308), AS160, p-GSK3β, p-JNK, TNFα, and IL-1β) was significantly different in the liver between treatment and control groups. In parallel, we observed that expression of genes in adipose tissues that are related to M1/M2 macrophages was differentially regulated by the different treatments. In summary, our study presents several lines of in vivo evidence that hyperinsulinemia and hyperandrogenism, either alone or in combination with insulin resistance, alter hepatic lipid metabolism, liver and adipose tissue inflammatory responses, and cellular function and that the effects of the different conditions are distinct from each other. By deciphering the metabolic, endocrine, and molecular alterations along with morphological changes, our findings offer a new understanding of how hyperandrogenism itself or combined with insulin resistance contributes to liver damage in women with PCOS.