High fat diet induced hepatic steatosis and insulin resistance: Role of dysregulated ceramide metabolism.
High fat diet induced hepatic steatosis and insulin resistance: Role of dysregulated ceramide metabolism.
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DOI：
10.1111/j.1872-034x.2011.00934.x
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
de la Monte SM
中科院分区：
文献类型：
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作者：
Longato L;Tong M;Wands JR;de la Monte SM
非酒精性脂肪性肝病（NAFLD）是一种胰岛素抵抗性疾病，可进展为肝硬化或肝功能衰竭。在NAFLD中，胰岛素抵抗使脂质代谢失调，增加了包括神经酰胺在内的细胞毒性脂质的产生，这加剧了肝脏胰岛素抵抗和损伤。Long Evans大鼠成对喂食低（LFD）或高（HFD）脂肪饮食8周。肝脏用于测量脂质、基因表达、胰岛素受体结合、胰岛素信号传导的完整性和促炎细胞因子。体外实验表征了神经酰胺对Huh7细胞活力、线粒体功能和胰岛素信号传导的影响。HFD喂养导致NAFLD伴外周和肝脏胰岛素抵抗，增加肝神经酰胺原基因表达，鞘磷脂酶活性和脂质过氧化，并增加血清神经酰胺。神经酰胺处理损害Huh7细胞活力、线粒体功能和胰岛素信号传导。肝脏神经酰胺生成和释放增加可能介导NAFLD中肝脏和外周胰岛素抵抗。
Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis or liver failure. In NAFLD, insulin resistance dysregulates lipid metabolism, increasing production of cytotoxic lipids including ceramides, which exacerbate hepatic insulin resistance and injury. Long Evans rats were pair-fed low (LFD) or high (HFD) fat diets for 8 weeks. Livers were used to measure lipids, gene expression, insulin receptor binding, integrity of insulin signaling, and pro-inflammatory cytokines. In vitro experiments characterized effects of ceramides on Huh7 cell viability, mitochondrial function, and insulin signaling. HFD feeding caused NAFLD with peripheral and hepatic insulin resistance, increased hepatic expression of pro-ceramide genes, sphingomyelinase activity, and lipid peroxidation, and increased serum ceramide. Ceramide treatment impaired Huh7 cell viability, mitochondrial function, and insulin signaling. Increased hepatic ceramide generation and release may mediate both hepatic and peripheral insulin resistance in NAFLD.