Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.Keywords:fatty liver disease;lipid metabolism;OTA;PPARKey Contribution:The in vitro and in vivo study reveal that OTA induces hepatic steatosis via PPARγ-CD36 axis. OTA prevents PPARγ from ubiquitination-mediated degradation by reducing the expression of the E3 ligase SIAH2 and SIAH2-PPARγ interaction.
Renal ischemia-reperfusion injury (IRI) is a prevalent clinical syndrome, yet its underlying pathogenesis remains largely unknown. Aldehyde dehydrogenase 2 (ALDH2), an enzyme responsible for detoxifying lipid aldehydes, has been suggested to play a protective role against IRI. In our study, we observed that Aldh2 knock-out C57BL/6 mice experienced more severe renal functional impairment following IRI. This was characterized by elevated levels of creatinine and blood urea nitrogen, as well as increased apoptosis. Proteomic analysis further revealed that ALDH2 deficiency significantly disrupted lipid metabolism, resulting in higher levels of the proinflammatory protein CYP4A and its metabolic byproduct, 20-HETE. This metabolic disruption exacerbated renal inflammation and triggered endoplasmic reticulum stress. However, we found that administration of the CYP4A inhibitor, HET0016, could ameliorate these effects. Mechanistically, we discovered that after IRI, ALDH2 translocates to the nucleus and interacts with nuclear receptor corepressor 1 (NCOR1) to repress Cyp4a transcription. ALDH2 specifically interacts with the N-terminal domain of NCOR1, which is responsible for its interaction with its E3 ligase SIAH2. This interaction inhibits the proteasome degradation of NCOR1, ultimately stabilizing the NCOR1 transcriptional repression complex. In summary, our research uncovers the role of ALDH2 in mitigating renal IRI by inhibiting 20-HETE synthesis through the transcriptional repression of Cyp4a .
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