Departments of Medicine, Pathology and Neurology, Divisions of Gastroenterology and Neuropathology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.
Hepatol Res. 2012 Apr;42(4):412-27. doi: 10.1111/j.1872-034X.2011.00934.x. Epub 2011 Dec 16.
Non-alcoholic fatty liver disease (NAFLD) is an insulin resistance disease that can progress to cirrhosis and liver failure. We hypothesized that 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.
High fat diet 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.
非酒精性脂肪性肝病（NAFLD）是一种胰岛素抵抗性疾病，可进展为肝硬化和肝功能衰竭。我们假设，在 NAFLD 中，胰岛素抵抗会使脂质代谢失调，增加细胞毒性脂质（包括神经酰胺）的产生，从而加剧肝脏胰岛素抵抗和损伤。
长爪沙鼠被给予低脂（LFD）或高脂（HFD）饮食 8 周。使用肝脏来测量脂质、基因表达、胰岛素受体结合、胰岛素信号的完整性和促炎细胞因子。体外实验研究了神经酰胺对 Huh7 细胞活力、线粒体功能和胰岛素信号的影响。
高脂饮食喂养导致 NAFLD 伴外周和肝脏胰岛素抵抗，肝内前神经酰胺基因表达增加，神经酰胺酶活性、脂质过氧化和血清神经酰胺增加。神经酰胺处理会损害 Huh7 细胞活力、线粒体功能和胰岛素信号。
肝内神经酰胺生成和释放的增加可能介导了 NAFLD 中的肝脏和外周胰岛素抵抗。
