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.

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.

Depression, as a common mental disorder, seriously endangers the health of the population, especially for adolescents. With the increasing prevalence of depression in adolescents and the limited use of antidepressant medications in adolescents, non-pharmacological treatments for adolescent depression also need to be explored more often. Beta-hydroxybutyric acid (BHB), the main active ingredient of the ketogenic diet, helps to protect neurological health, but whether it has a mitigating effect on depression in adolescents remains unclear. In this study, we investigated the mitigating effect of BHB on depressive-like behavior in adolescence and its underlying mechanisms. Mice were subjected to chronic unpredictable mild stress (CUMS) for modeling depression, and BHB (200 mg/kd/d) were administrated to mice for 10 days after CUMS. First, behavioral experiments, including the open-field test (OFT), elevated plus maze test (EPM), tail suspension test (TST), and sucrose preference test (SPT), revealed that BHB supplementation significantly restored anxiety- and depression-like phenotypes in mice. Further investigation using fiber photometry technology demonstrated that BHB restored the excitatory neuronal response in the medial prefrontal cortex (mPFC) during the TST, as evidenced by increased peak latency and amplitude of neuronal activity. Electrophysiological and morphological analyses further showed that BHB rescued CUMS-induced impairments in synaptic transmission, as indicated by increased frequency of miniature excitatory postsynaptic currents (mEPSC), and restored dendritic spine density in the mPFC. Synaptic structures and functions could be regulated by microglial engulfment. Mechanistically, BHB reduced the expression of Iba1 and restored microglial branching in CUMS mice, which suggested that BHB suppressed the pro-inflammatory polarization of microglia. Importantly, BHB decreased the expression of complement 3 (C3) and CD18 (a subunit of C3 receptors), suggesting that BHB may inhibit C3-mediated microglial engulfment of neuronal synapses. These findings demonstrate that BHB mitigates anxiety- and depression-like behaviors by impeding C3-mediated microglial engulfment in the mPFC. Collectively, BHB may represent a promising therapeutic approach for alleviating complement-related anxiety and depression, shedding light on novel strategies for neurodevelopmental and neuropsychiatric disorders.