Ablation of carotenoid cleavage enzymes (BCO1 and BCO2) induced hepatic steatosis by altering the farnesoid X receptor/miR-34a/sirtuin 1 pathway
Ablation of carotenoid cleavage enzymes (BCO1 and BCO2) induced hepatic steatosis by altering the farnesoid X receptor/miR-34a/sirtuin 1 pathway
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DOI：
10.1016/j.abb.2018.07.007
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发表时间：
2018-09-15
影响因子：
3.9
通讯作者：
Wang, Xiang-Dong
中科院分区：
文献类型：
--
作者：
Lim, Ji Ye;Liu, Chun;Wang, Xiang-Dong
-胡萝卜素- 15,15 '-加氧酶（BCO1）和-胡萝卜素-9',10'-加氧酶（BCO2）是类胡萝卜素代谢的必需酶。虽然BCO1/BCO2多态性与人类和动物类胡萝卜素水平的改变有关，但实验研究表明，BCO1和BCO2可能具有除类胡萝卜素裂解外的特殊生理功能。在本研究中，我们研究了消融BCO1/BCO2在非酒精性脂肪性肝病（NAFLD）发展中的作用及其潜在的分子机制。BCO1/BCO2双敲除（DKO）小鼠出现肝脏脂肪变性（8/8），与WT（0/8）相比，肝脏和血浆甘油三酯和总胆固醇水平显著升高。BCO1/BCO2 DKO小鼠的肝脏变化与显著相关：1)脂肪生成标志物升高，脂肪酸（3-氧化标志物）降低；2)胆固醇代谢标志物上调；3)与TG积累和胆固醇代谢相关的microrna的改变；4)肝脏氧化应激标志物HO-1升高，抗氧化酶降低；5) farnesoid X受体（FXR）、小异二聚体伴侣（SHP）和sirtuin 1 （SIRT1）降低。本研究提供了新的实验证据，表明BCO1和BCO2可能通过调控FXR/miR-34a/SIRT1通路，在维持正常的肝脏脂质和胆固醇稳态中发挥重要作用。
beta-Carotene-15, 15'-oxygenase (BCO1) and beta-carotene-9', 10'-oxygenase (BCO2) are essential enzymes in carotenoid metabolism. While BCO1/BCO2 polymorphisms have been associated with alterations to human and animal carotenoid levels, experimental studies have suggested that BCO1 and BCO2 may have specific physiological functions beyond the cleavage of carotenoids. In the present study, we investigated the effect of ablation of both BCO1/BCO2 in the development of non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism(s). BCO1/BCO2 double knock out (DKO) mice developed hepatic steatosis (8/8) and had significantly higher levels of hepatic and plasma triglyceride and total cholesterol compared to WT (0/8). Hepatic changes in the BCO1/BCO2 DKO mice were associated with significant: 1) increases in lipogenesis markers, and decreases in fatty acid (3-oxidation markers; 2) upregulation of cholesterol metabolism markers; 3) alterations to microRNAs related to TG accumulation and cholesterol metabolism; 4) increases in an hepatic oxidative stress marker (HO-1) but decreases in anti-oxidant enzymes; and 5) decreases in farnesoid X receptor (FXR), small heterodimer partner (SHP), and sirtuin 1 (SIRT1). The present study provided novel experimental evidence that BCO1 and BCO2 could play a significant role in maintaining normal hepatic lipid and cholesterol homeostasis, potentially through the regulation of the FXR/miR-34a/SIRT1 pathway.