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    Dietary alkaloid nuciferine isolated from the leaves of Nelumbo nucifera can ameliorate dyslipidemia and liver lipid accumulation, but the underlying mechanism remains unclear. Caspase recruitment domain protein family member 6 (CARD6) is suggested to play an important role in metabolic diseases. This study aimed to investigate the role and the upstream regulator of CARD6 in high fructose-induced liver lipid accumulation and whether and how the anti-lipid accumulation effect of nuciferine was related to CARD6. Herein, we found that high fructose decreased CARD6 expression and increased ASK1 and JNK1/2 phosphorylation in rat livers and hepatocytes, which were attenuated by nuciferine. Furthermore, after the transfection with HA-CARD6, CARD6 siRNA and MIB2 siRNA, the data showed that CARD6 overexpression blocked high fructose-induced upregulation of ASK1 and JNK1/2 phosphorylation as well as lipid accumulation in hepatocytes. CARD6 siRNA reversed the amelioration of nuciferine to high fructose-induced upregulation of ASK1 and JNK1/2 phosphorylation in hepatocyte lipid accumulation. Mechanistically, high fructose upregulated MIB2 expression by interacting with CARD6 and promoting K48-linked CARD6 polyubiquitination and degradation in high fructose-stimulated hepatocytes which were explored by immunoblotting, immunofluorescence, and immunoprecipitation. However, MIB2 siRNA reversed high fructose-induced downregulation of CARD6 and lipid accumulation in hepatocytes. Notably, nuciferine reduced MIB2 expression and thus decreased K48-linked CARD6 polyubiquitination and degradation in the amelioration of high fructose-induced lipid accumulation in hepatocytes. These results suggested that nuciferine exhibited a protective effect against high fructose-induced liver lipid accumulation through blocking MIB2-mediated CARD6 polyubiquitination and degradation.

    Citation

    Feng Li, Xiaojuan Zhao, Fengyu Xie, Zixuan Wang, Hong Ding, Wanru Wang, Ruiqing Jiao, Ying Pan, Lingdong Kong. Nuciferine blocks MIB2-mediated CARD6 polyubiquitination and degradation in the amelioration of high fructose-induced liver lipid accumulation. Food & function. 2023 May 22;14(10):4706-4721

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    PMID: 37186242

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