Resveratrol attenuates efavirenz-induced hepatic steatosis and hypercholesterolemia in mice by inhibiting pregnane X receptor activation and decreasing inflammation

Efavirenz (EFV), a widely prescribed antiviral medication, has been implicated in dyslipidemia and can activate the pregnane X receptor (PXR), leading to hepatic steatosis and hypercholesterolemia in mice. Resveratrol (RES) can ameliorate hepatic steatosis and functions as a partial PXR agonist, capable of mitigating PXR expression induced by other PXR agonists. Therefore, we hypothesized that RES could attenuate EFV-induced hepatic steatosis and hypercholesterolemia by downregulating PXR expression and suppressing inflammatory cytokine levels. Herein, we conducted an in vivo study involving six-week-old male mice, which were divided into four groups for a seven-day intervention: control (CTRL, carrier solution), EFV (80 mg/kg), RES (50 mg/kg), and RES + EFV groups. Serum and hepatic tissue samples were collected to assess cholesterol and triglyceride levels. Hepatic lipid accumulation was evaluated through hematoxylin-eosin and oil red O staining. Polymerase chain reaction and western blot were performed to quantify hepatic inflammatory factors, lipogenic gene expression, and PXR levels. Our results indicated that hepatic lipid droplet accumulation was reduced in the RES + EFV group compared to the EFV group. Similarly, the levels of hepatic inflammatory factors were attenuated in the RES + EFV group relative to the EFV group. Furthermore, RES counteracted the upregulation of hepatic lipid-metabolizing enzymes induced by EFV at both the transcriptional and protein levels. Importantly, PXR expression was downregulated in the RES + EFV group compared to the EFV group. Conclusively, our findings suggest that RES effectively mitigates EFV-induced hepatic steatosis and hypercholesterolemia by inhibiting PXR activation and decreasing inflammation.