CPT1A-dependent BHB synthesis mediates BPA-induced hepatic metabolic dysfunction

Bisphenol A (BPA) is an environmental endocrine disruptor closely associated with metabolic disorders in humans. Our previous studies showed that early-life exposure to BPA disrupts lipid homeostasis in male mice. However, the underlying mechanisms responsible for its metabolic dysfunction in adulthood are still not fully understood. Here, we demonstrated that BPA disrupts hepatic lipid metabolism through metabolomics in conjunction with related studies. Furthermore, we found that BPA disrupts hepatic beta-hydroxybutyrate (BHB) metabolism, as evidenced by significantly reduced hepatic and intracellular BHB levels and the inhibition of key ketogenic enzymes, including 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) and 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2). Then, we further found that exogenous BHB intervention could effectively alleviate BPA-induced hepatic metabolic disorders, through reducing aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, and hepatocyte lipid deposition. Mechanistic studies showed that BPA exposure significantly inhibited the expression of carnitine palmitoyltransferase 1A (CPT1A) which plays a key role in the BHB metabolic axis, whereas up regulation of CPT1A using the agonist of CPT1A improved fatty acid β-oxidation, and reduced the level of intracellular lipids. In summary, our findings from a metabolic perspective demonstrate that BPA induces hepatic metabolic dysfunction in adult mice, and that this disruption can be alleviated by BHB via CPT1A-mediated stimulation of fatty acid oxidation.