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首页> 外文期刊>Cell metabolism >CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance
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CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance

机译：CerS2单倍剂量不足会抑制β-氧化并赋予对饮食性脂肪性肝炎和胰岛素抵抗的敏感性

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摘要

Inhibition of ceramide synthesis prevents diabetes, steatosis, and cardiovascular disease in rodents. Six different ceramide synthases (CerS) that differ in tissue distribution and substrate specificity account for the diversity in acyl-chain composition of distinct ceramide species. Haploinsufficiency for ceramide synthase 2 (CerS2), the dominant isoform in the liver that preferentially makes very-long-chain (C22/C24/C24:1) ceramides, led to compensatory increases in long-chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance. Mechanistic studies revealed that these metabolic effects were likely due to impaired β-oxidation resulting from inactivation of electron transport chain components. Inhibiting global ceramide synthesis negated the effects of CerS2 haploinsufficiency in vivo, and increasing C16-ceramides by overexpressing CerS6 recapitulated the phenotype in isolated, primary hepatocytes. Collectively, these studies reveal that altering sphingolipid acylation patterns impacts hepatic steatosis and insulin sensitivity and identify CerS6 as a possible therapeutic target for treating metabolic diseases associated with obesity.
机译：抑制神经酰胺合成可防止啮齿动物患糖尿病，脂肪变性和心血管疾病。六个不同的神经酰胺合酶（CerS）在组织分布和底物特异性方面不同，这说明了不同的神经酰胺种类在酰基链组成上的多样性。神经酰胺合酶2（CerS2）的单倍剂量不足，这是肝脏中优先形成超长链（C22 / C24 / C24：1）神经酰胺的显性同种型，导致长链C16神经酰胺的代偿性增加并赋予饮食易感性引起的脂肪性肝炎和胰岛素抵抗。机理研究表明，这些代谢作用可能是由于电子传输链成分失活导致的β-氧化受损。抑制全局神经酰胺合成可消除体内CerS2单倍剂量不足的影响，并通过过度表达CerS6来增加C16-神经酰胺，概括了分离的原代肝细胞的表型。这些研究共同表明，改变鞘脂酰化方式会影响肝脂肪变性和胰岛素敏感性，并确定CerS6是治疗与肥胖相关的代谢性疾病的可能治疗靶标。

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