■依泽蒂米贝,通过阻断肠道胆固醇转运蛋白Niemann-PickC1等1来降低胆固醇,据报道可减少人类和动物的肝脂肪变性。这里,我们证明了肝脏代谢产物和脂质的变化,并解释了依泽替米贝在肝性脂肪变性中的潜在机制。
■我们通过胃管饲喂高脂饮食(60kcal%脂肪)或媒介物(对照)或依泽替米贝(10mgkg-1)给大津长埃文斯德岛脂肪(OLETF)大鼠喂食12周,并对肝组织进行全面的代谢和脂质组学分析。我们用了大鼠肝脏组织,HepG2肝癌细胞系,和siRNA来探索潜在的机制。
■在高脂饮食的OLETF大鼠中,依泽替米贝显示代谢参数改善和肝脏脂肪积累减少。全面的代谢组学和脂质组学分析揭示了磷脂的显着变化,特别是磷脂酰胆碱(PC),和肝PC中脂酰链组成的改变。涉及大鼠肝组织基因表达和甘油三酯评估的进一步分析,HepG2肝癌细胞系,和siRNA实验揭示了依泽替米贝的机制涉及关键磷脂生物合成基因的上调,CTP:α磷酸胆碱磷脂酰转移酶和N-甲基转移酶,和磷脂重塑基因溶血磷脂酰胆碱酰基转移酶3。
■这项研究表明,依泽替米贝通过影响磷脂的组成和水平来改善代谢参数并减少肝脏脂肪积累,特别是磷脂酰胆碱,并通过上调与磷脂生物合成和重塑相关的基因。这些发现为依泽替米贝减轻肝脏脂肪积累的分子途径提供了有价值的见解,强调磷脂代谢的作用。
UNASSIGNED: Ezetimibe, which lowers cholesterol by blocking the intestinal cholesterol transporter Niemann-Pick C1 like 1, is reported to reduce hepatic steatosis in humans and animals. Here, we demonstrate the changes in hepatic metabolites and lipids and explain the underlying mechanism of ezetimibe in hepatic steatosis.
UNASSIGNED: We fed Otsuka Long-Evans Tokushima Fatty (OLETF) rats a high-fat diet (60 kcal % fat) with or vehicle (control) or ezetimibe (10 mg kg-1) via stomach gavage for 12 weeks and performed comprehensive metabolomic and lipidomic profiling of liver tissue. We used rat liver tissues, HepG2 hepatoma cell lines, and siRNA to explore the underlying mechanism.
UNASSIGNED: In OLETF rats on a high-fat diet, ezetimibe showed improvements in metabolic parameters and reduction in hepatic fat accumulation. The comprehensive metabolomic and lipidomic profiling revealed significant changes in
phospholipids, particularly phosphatidylcholines (PC), and alterations in the fatty acyl-chain composition in hepatic PCs. Further analyses involving gene expression and triglyceride assessments in rat liver tissues, HepG2 hepatoma cell lines, and siRNA experiments unveiled that ezetimibe\'s mechanism involves the upregulation of key phospholipid biosynthesis genes, CTP:phosphocholine cytidylyltransferase alpha and phosphatidylethanolamine N-methyl-transferase, and the phospholipid remodeling gene lysophosphatidylcholine acyltransferase 3.
UNASSIGNED: This study demonstrate that ezetimibe improves metabolic parameters and reduces hepatic fat accumulation by influencing the composition and levels of
phospholipids, specifically phosphatidylcholines, and by upregulating genes related to phospholipid biosynthesis and remodeling. These findings provide valuable insights into the molecular pathways through which ezetimibe mitigates hepatic fat accumulation, emphasizing the role of phospholipid metabolism.