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Non-alcoholic fatty liver disease (NAFLD) is now a public health issue worldwide, but no drug has received approval yet. Here we demonstrated that genistein, an isoflavonoid derived from soybean, effectively attenuated high fat diet-induced NAFLD progression by targeting thromboxane A2 (TXA2) pathway. Analysis of profile of eicosanoid synthesis pathways in liver unexpectedly revealed that TXA2 pathway was aberrantly active in NAFLD. Switching off TXA2 biosynthesis by aspirin effectively suppressed high-fat induced NAFLD progression. In parallel, genistein was identified as a natural thromboxane A2 receptor (TBXA2R) antagonist and successfully applied in NAFLD prevention. Phenotypically, treatment with either aspirin or genistein suppressed body weight gain, attenuated liver steatosis, normalized aminotransferase abnormalities and improved glucose tolerance. Further mechanism study suggested that TXA2 pathway was required for tumor necrosis factor-alpha (TNF-α) induced hepatic insulin resistance. Collectively, our findings established the critical pathophysiological role of the TXA2 pathway in NAFLD, and provided a rationale for introducing a strategy targeting TXA2 for NAFLD prevention and management. |
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Keywords:Aspirin; Genistein; NAFLD; TXA2; Insulin resistant |
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