Pioglitazone can improve liver sex hormone-binding globulin levels and lipid metabolism in polycystic ovary syndrome by regulating hepatocyte nuclear factor-4α

Abstract

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder that is closely correlated with insulin resistance. Sex hormone-binding globulin (SHBG) is an important carrier for regulating androgen activity and is affected by insulin level, which is related to metabolic abnormalities and long-term prognosis of PCOS. Insulin sensitizer pioglitazone can improve the SHBG level and dyslipidaemia in PCOS, but the mechanism remains unclear. We investigated liver SHBG expression, liver lipid levels, and the effects and potential mechanisms of pioglitazone on reproductive and metabolic disorders in a rat model of polycystic ovary syndrome with insulin resistance (PCOS-IR). PCOS-IR was induced by letrozole and a high-fat diet. Metformin was used as a positive control. Additionally, dihydrotestosterone and oleic acid combined with palmitic acid were used to induce the HepG2 cell models with IR. The cells were exposed to pioglitazone alone or in combination with a hepatocyte nuclear factor (HNF)− 4α inhibitor. Changes in biochemical characteristics were analysed using an enzyme-linked immunosorbent assay. Vaginal smears were used to analyse the oestrous cycle, and ovarian histology was used to analyse the changes in ovarian morphology. The degree of IR in vivo and in vitro was measured using the hyperinsulinaemic-euglycaemic clamp and glucose oxidase techniques. The levels of key anabolism-related proteins, including SHBG, HNF-4α, and peroxidase proliferator-activated receptor (PPAR-γ), were measured using western blots. Pioglitazone and metformin significantly increased the SHBG levels in the sera and livers. Compared to metformin, pioglitazone significantly improved the lipid droplet deposition, triglyceride (TG) and total cholesterol (TC) levels, HNF-4α protein expression, and weights of the livers in the PCOS-IR rats. After applying pioglitazone with an HNF-4α inhibitor in the PCOS-IR cell models, we found that pioglitazone may increase SHBG and improve IR, TG, and TC levels by upregulating HNF-4α. Similar to metformin, pioglitazone also restored the oestrous cycle and ovarian morphology, ameliorated IR and hyperandrogenaemia in the PCOS-IR rats. Our findings hint at the value of HNF-4α in the treatment of PCOS by PIO, which could shed light on potential targets that may be used in treatments for PCOS with metabolic disorders.