Decreased PPARβ in hepatocytes specifically determines BPA-induced selective accumulation of liver glycerolipid and cholesterol esters

The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is driven by endogenous risk factors. Bisphenol A (BPA), an endocrine disruptor chemical commonly found in food packaging, although it has been clearly defined as a typical risk factor for MASLD, the lipid-specific and cell-specific mechanisms leading to hepatic steatosis remain unclear. Our results showed that BPA exposure induced significant hepatic steatosis and dyslipidemia in C57BL/6 male mice. Furthermore, lipid composition analysis revealed that BPA induced specific accumulation of cholesteryl esters (CE 20:6 and CE 19:0) and glycerolipid subclasses (TAG and DG), rather than phospholipids. Furthermore, decreased peroxisome proliferator-activated receptorβ (PPARβ) results in over-synthesis of cholesterol and glycerolipid, and reduced fatty acid oxidation. Overexpression of PPARβ alleviated BPA-induced lipid dysregulation by disrupting the INSIG/SREBP pathway, a critical regulator of glycerolipid and cholesterol esters synthesis. Besides, BPA-induced hepatic steatosis presents significant cell-type specificity. The abnormal expression of PPARβ and lipid accumulation were only observed in hepatocytes rather than non-parenchymal cells. More deeply, PPARβ overexpression in hepatocytes attenuated BPA-induced steatosis, whereas its knockdown exacerbated lipid dysregulation, underscoring its essential and cell-type-specific role in maintaining hepatic lipid homeostasis. These findings provide important insights into the mechanisms of hepatic lipid dysregulation caused by BPA and highlight the protective effect of PPARβ in lipid metabolism. This provides a crucial theoretical foundation for preventing liver diseases associated with contaminants in food packaging.