HA-20 prevents hepatocyte steatosis in metabolic-associated fatty liver disease via regulating Ca2+ relative signalling pathways.
HA-20 prevents hepatocyte steatosis in metabolic-associated fatty liver disease via regulating Ca2+ relative signalling pathways.
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DOI：
10.1016/j.ejphar.2022.174838
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发表时间：
2022-02
影响因子：
5
通讯作者：
Jie Wang;Ming Du;Yun Du;Jian-Xin Li
中科院分区：
文献类型：
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作者：
Jie Wang;Ming Du;Yun Du;Jian-Xin Li
代谢相关性脂肪肝（MAFLD）是由肝细胞脂肪变性引起的，与肥胖、II型糖尿病和心脏病有关。目前还没有有效的药物来治疗MAFLD。本研究探讨了HA-20（一种油酸衍生物）对MAFLD中肝细胞脂肪变性的影响。用油酸培养HepG 2、L02和AML 12细胞用于体外MAFLD细胞测定，并建立高脂饮食+高果糖饮食诱导（HFHF）MAFLD小鼠模型用于体内研究。结果表明，HA-20在细胞试验中可预防肝细胞脂肪变性，并在5.0、10.0和20.0 μM HA-20组中分别对甘油三酯（TG）水平产生26.3%、57.7%和70.0%的抑制。HA-20对HepG 2、L02和AML 12细胞的EC 50值分别为9.7 ± 0.6 μM、42.4 ± 3.5 μM和71.0 ± 14.7 μM。HA-20还可预防MAFLD小鼠模型中的肝细胞脂肪变性，2.5和5.0 mg/kg/天HA-20组的肝脏甘油三酯含量分别为2.3 ± 0.4和1.5 ± 0.2 mmol/L，低于HFHF组的6.2 ± 0.7 mmol/L和二甲双胍组的3.3 ± 0.4 mmol/L。进一步的机制研究表明，HA-20增加钙调蛋白依赖性蛋白激酶激酶（p-CaMKK）的磷酸化和AMP激活的蛋白激酶（p-AMPK）的磷酸化，至少部分是通过增加细胞内Ca 2+浓度，从而抑制脂肪生成和增强β-氧化。我们的研究结果为通过增加Ca 2+预防MAFLD提供了新的见解，并表明HA-20具有治疗MAFLD的潜力。
Metabolic-associated fatty liver disease (MAFLD) is caused by hepatocyte steatosis and is associated with obesity, type II diabetes, and heart disease. There are currently no effective drugs to treat MAFLD. This study explored the effect of HA-20, an oleanolic acid derivative, on hepatocyte steatosis in MAFLD. HepG2, L02, and AML12 cells were developed using oleic acid forin vitroMAFLD cell assays, and a high-fat diet + high-fructose diet-induced (HFHF) MAFLD mouse model was established forin vivostudies. The results demonstrated that HA-20 prevented hepatocyte steatosis in cell assays and caused 26.3, 57.7 and 70.0% inhibition of triglyceride (TG) levels in the 5.0, 10.0 and 20.0 μM HA-20 groups, respectively. The EC50values of HA-20 treatment in HepG2, L02 and AML12 cells were 9.7 ± 0.6 μM, 42.4 ± 3.5 μM and 71.0 ± 14.7 μM, respectively. HA-20 also prevented hepatocyte steatosis in the MAFLD mouse model, the liver triglyceride contents were 2.3 ± 0.4 and 1.5 ± 0.2 mmol/L in the 2.5 and 5.0 mg/kg/day HA-20 groups, lower than 6.2 ± 0.7 mmol/L in the HFHF group and 3.3 ± 0.4 mmol/L in the metformin group. Further mechanistic investigation revealed that HA-20 increased the phosphorylation of calmodulin-dependent protein kinase kinase (p-CaMKK) and the phosphorylation of AMP-activated protein kinase (p-AMPK), at least partially by increasing intracellular Ca2+concentration, which suppressed lipogenesis and enhanced β-oxidation. Our findings provide new insight into preventing MAFLD by increasing Ca2+and suggest that HA-20 possesses therapeutic potential for MAFLD management.