Abstract：
Tamoxifen is an estrogen receptor modulator that has been reported to alleviate hepatic lipid accumulation in mice, but the mechanism is still unclear. Peroxisome fatty acid β-oxidation is the main metabolic pathway for the overload of long-chain fatty acids. As long-chain fatty acids are a cause of hepatic lipid accumulation, the activation of peroxisome fatty acid β-oxidation might be a novel therapeutic strategy for metabolic associated fatty liver disease. In this study, we investigated the mechanism of tamoxifen against hepatic lipid accumulation based on the activation of peroxisome fatty acid β-oxidation. Tamoxifen reduced liver long-chain fatty acids and relieved hepatic lipid accumulation in high fat diet mice without sex difference. In vitro, tamoxifen protected primary hepatocytes against palmitic acid-induced lipotoxicity. Mechanistically, the RNA-sequence of hepatocytes isolated from the liver revealed that peroxisome fatty acid β-oxidation was activated by tamoxifen. Protein and mRNA expression of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase were significantly increased in vivo and in vitro. Small interfering RNA enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase in primary hepatocytes abolished the therapeutic effects of tamoxifen in lipid accumulation. In conclusion, our results indicated that tamoxifen could relieve hepatic lipid accumulation in high fat diet mice based on the activation of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase-mediated peroxisome fatty acids β-oxidation.
摘要：
他莫昔芬是一种雌激素受体调节剂，据报道可缓解小鼠肝脏脂质积聚，但机制尚不清楚。过氧化物酶体脂肪酸β-氧化是长链脂肪酸超负荷的主要代谢途径。由于长链脂肪酸是肝脏脂质积累的原因，过氧化物酶体脂肪酸β-氧化的激活可能是代谢相关脂肪肝疾病的一种新的治疗策略.在这项研究中,我们基于过氧化物酶体脂肪酸β-氧化的激活，研究了他莫昔芬抗肝脏脂质积累的机制。在无性别差异的高脂饮食小鼠中，他莫昔芬降低肝脏长链脂肪酸并减轻肝脏脂质积累。体外，他莫昔芬保护原代肝细胞免受棕榈酸诱导的脂毒性。机械上,从肝脏分离的肝细胞的RNA序列显示过氧化物酶体脂肪酸β-氧化被他莫昔芬激活。烯酰辅酶A水合酶和3-羟基酰基辅酶A水合酶的蛋白和mRNA表达在体内和体外均显着增加。原代肝细胞中的小干扰RNA烯酰CoA水合酶和3-羟酰基CoA水合酶消除了他莫昔芬在脂质积累中的治疗作用。总之,我们的结果表明,他莫昔芬可以通过激活烯酰辅酶A水合酶和3-羟酰基辅酶A水合酶介导的过氧化物酶体脂肪酸β-氧化来减轻高脂饮食小鼠的肝脏脂质积累.
