N-acetylcysteine ameliorates oxidative stress-induced decline in sex hormone-binding globulin in HepG2 cells and polycystic ovary syndrome rats

Background Low sex hormone-binding globulin (SHBG) levels are a significant indicator of hyperandrogenism severity in patients with polycystic ovary syndrome (PCOS) and are associated with an increased risk of reproductive and metabolic diseases. Oxidative stress suppresses the production and secretion of SHBG. However, the effect of the antioxidant N-acetylcysteine (NAC) on hepatic SHBG expression remains unknown. This study investigated the effects of NAC on SHBG expression and the underlying mechanism in HepG2 cells and a rat model of PCOS. Methods HepG2 cells were treated with testosterone propionate (TP), oxidized high-density lipoprotein (ox-HDL), oxidized low-density lipoprotein (ox-LDL), and NAC. Female Sprague-Dawley rats aged 28 days were randomly allocated to eight groups: control, PCOS, and control and PCOS groups treated with NAC at 100, 200, or 400 mg/kg body weight. The PCOS rat model, induced by TP and a high-fat, high-sugar diet, was treated with different doses of NAC for 8 weeks. The expression of SHBG, hepatocyte nuclear factor 4α (HNF4α), chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1), and peroxisome proliferator-activated receptor-γ (PPAR-γ) was assessed in HepG2 cells and rat liver tissue. Metabolic, hormonal, and oxidative stress indices were analyzed in the rat model. Results In HepG2 cells, TP and oxidized lipoprotein treatments significantly suppressed SHBG and HNF4α expression, while NAC treatment reversed the inhibitory effects induced by ox-HDL and ox-LDL ( P < 0.05). In PCOS rats, NAC intervention increased the mRNA and protein levels of SHBG by upregulating HNF4α and downregulating COUP-TF1 and PPAR-γ expression in the liver; increased serum SHBG; reduced hepatocytic reactive oxygen species levels ( P < 0.05); and ameliorated obesity, estrous cycle abnormalities, hepatic steatosis, circulating sex hormone levels, and the lipid profile, with 200 mg/kg NAC showing the most favorable overall pattern among the three doses tested. Conclusion NAC treatment ameliorates oxidative stress-induced decreases in SHBG and HNF4α expression in HepG2 cells and may restore hepatocytic SHBG production by upregulating HNF4α and downregulating COUP-TF1/PPAR-γ expression in rats with PCOS.