Hepatic dysmetabolism in polycystic ovarian syndrome: impact of paraoxonase-1 modulation by butyrate

The complications of endocrine-metabolic disorders among women of reproductive age, inclusively polycystic ovarian syndrome (PCOS), are cascade of events leading to cardiovascular diseases, as well as non-alcoholic fatty liver disease (NAFLD) which is the leading cause of liver cirrhosis and hepatic carcinoma that often necessitates organ transplant. Paraoxonase-1 (PON-1) has been shown to be protective against metabolic assaults. However, its role in hepatic glucolipid regulation, particularly in PCOS model, has not been documented. Short-chain fatty acid (SCFAs) are essential modulators of metabolic health. The present study hypothesizes that butyrate would ameliorate hepatic dysmetabolism by upregulation of PON-1. Female Wistar rats (8 weeks old) were allotted into groups: control (CTL), butyrate (BUT), letrozole (LET), and LET + BUT. Letrozole (1 mg/kg) was administered for 21 days to induce PCOS. Thereafter, butyrate (200 mg/kg) was administered for 6 weeks. The animals were sacrificed and biochemical assays; histological and immunohistochemical evaluations were performed with appropriate methods. Rats with PCOS showed cystic ovaries, hyperandrogenism, reduced insulin sensitivity, hyperleptinemia, hypoadiponectinemia, dyslipidemia, and hepatic lipid peroxidation/lipotoxicity, as well as increased hepatic caspase-6, proinflammatory markers (NF-kB, SDF-1), decreased antioxidant defense (NrF2), and HIF-1α, with corresponding expression of inflammasome as evaluated immunohistochemically. These alterations were accompanied by a suppressed level of PON-1. However, the administration of butyrate attenuated these hepatic metabolic and cellular perturbations. Results from this study demonstrate that butyrate protects against hepatic glucolipid dysregulation and its comorbid oxidative stress and inflammation in the PCOS model by the modulation of PON-1. © The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature 2024.