Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2 HKO ) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2 HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.
Bisphenol A (BPA) is a well-known endocrine-disrupting pollutant that poses significant environmental challenges globally. However, the toxicity of nitro-BPA (NBPA), the primary transformation product of BPA, remains poorly understood. This study employs a multi-omics approach, integrating in silico and bioinformatics analyses, to investigate and compare the male reproductive toxicity of BPA and NBPA in male zebrafish exposed to environmentally relevant concentrations. After 21 days of exposure, we observed a significant increase in cumulative egg production over five days in the NBPA 200 nM group compared to pre-exposure levels. Conversely, the gonadosomatic index of NBPA 200 nM group was significantly reduced by approximately 41.65 %. Our findings indicate that the activation of ESRRγ and inhibition of NR5A2 are critical molecular initiating events linked to male reproductive toxicity. Additionally, both BPA and NBPA were found to disrupt several key events within the steroid hormone biosynthesis pathway. This disruption includes the downregulation of genes encoding cytochrome P450 (CYP450) and hydroxysteroid dehydrogenase enzymes, as well as alterations in the levels of steroid hormones such as cholesterol and 25-hydroxycholesterol. Our study identifies biomolecular targets of BPA and NBPA at environmentally relevant concentrations that induce reproductive toxicity, enhancing our understanding of NBPA toxicity and are anticipated to inform the development of effective mitigation strategies.
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