Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
FASEB J. 2018 Jan;32(1):130-142. doi: 10.1096/fj.201601142R. Epub 2017 Sep 1.
Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis and and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. ceramide reduction by inhibition of ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis.-Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.
perilipin 2 (PLIN2) 是一种脂肪滴蛋白，在酒精性脂肪变性中上调，与肝内神经酰胺的积累有关，神经酰胺是一种与酒精性肝病发病机制有关的生物活性脂质。神经酰胺合成酶在调节 PLIN2 和促进肝细胞脂质积累中的具体作用尚不清楚。我们研究了药理抑制神经酰胺合成对酒精性脂肪变性小鼠和乙醇孵育的人肝癌 VL17A 细胞中肝 PLIN2 表达、脂肪变性以及葡萄糖和脂质代谢平衡的影响。在细胞中，药理抑制神经酰胺合酶通过降低 PLIN2 RNA 稳定性来减少脂质积累。亚型神经酰胺合酶（CerS）6 在实验性酒精性脂肪变性中特异性上调，并且在人类酒精性脂肪变性的 3 区肝细胞中上调。通过抑制神经酰胺合成减少 ceramide 可降低酒精喂养小鼠的 PLIN2 和肝脂肪变性，但只有 合成抑制而非鞘磷脂水解可改善葡萄糖耐量和血脂异常。这些发现提示 CerS6 是 PLIN2 的新型调节剂，并表明神经酰胺合成酶可能促进酒精性肝病的最早阶段，即酒精性脂肪变性。-Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.
