Ceramide plays pathogenic roles in nonalcoholic fatty liver disease (NAFLD) via multiple mechanisms, and as such inhibition of ceramide de novo synthesis in the liver may be of therapeutically beneficial in patients with NAFLD. In this study, we aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. Sprague Dawley rats were randomly divided into three groups: standard chow (n = 10), high-fat diet (HFD) (n = 10) or HFD combined with oral administration of myriocin (0.3 mg/kg on alternate days for 8 weeks) (n = 10). Liver histology and autophagy function were measured. HepG2 cells were incubated with fatty acid with or without myriocin treatment. Lipid accumulation and autophagy markers in the HepG2 cells were analyzed. Serum ceramide changes were studied in 104 subjects consisting healthy adults, liver biopsy-proven patients with NAFLD and liver biopsy-proven patients with chronic hepatitis B (CHB). Myriocin reversed the elevated body weight and serum transaminases and alleviated dyslipidemia in HFD fed rats. Myriocin treatment significantly attenuated liver pathology including steatosis, lobular inflammation and ballooning. By qPCR analysis, it was revealed that myriocin corrected the expression pattern of fatty acid metabolism associated genes including Fabp1, Pparα, Cpt-1α and Acox-2. Further, myriocin also restored the impaired hepatic autophagy function in rats with HFD-induced NASH, and this has been verified in HepG2 cells. Among the sphingolipid species that we screened in lipidomic profiles, significantly increased ceramide was observed in NASH patients as compared to the controls and non-NASH patients, regardless of whether or not they have active CHB. Ceramide may play an important regulatory role in the autophagy function in the pathogenesis of NASH. Hence, blockade of ceramide signaling by myriocin may be of therapeutically beneficial in NASH. Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.

中文翻译：

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Myriocin在非酒精性脂肪性肝炎中的治疗作用和自噬调节

神经酰胺通过多种机制在非酒精性脂肪肝疾病（NAFLD）中发挥致病作用，因此抑制肝脏中的神经酰胺从头合成可能对NAFLD患者具有治疗益处。在这项研究中，我们旨在探讨通过抑制自噬，肉豆蔻酸抑制神经酰胺信号传导在NAFLD动物模型中是否有益。将Sprague Dawley大鼠随机分为三组：标准食物（n = 10），高脂饮食（HFD）（n = 10）或HFD联合口服Myriocin（隔8天每隔0.3 mg / kg） （n = 10）。测量肝组织学和自噬功能。将HepG2细胞与经过或不经过myriocin处理的脂肪酸一起孵育。分析了HepG2细胞中的脂质蓄积和自噬标记。在104名受试者中研究了血清神经酰胺的变化，这些受试者包括健康成年人，经肝活检证实的NAFLD患者和经肝活检证实的慢性乙型肝炎（CHB）患者。Myriocin逆转了HFD喂养大鼠的体重和血清转氨酶升高，并减轻了血脂异常。肌球蛋白治疗可显着减轻肝脏病理，包括脂肪变性，小叶发炎和球囊扩张。通过qPCR分析，揭示了肉豆蔻酸校正了脂肪酸代谢相关基因包括Fabp1，Pparα，Cpt-1α和Acox-2的表达模式。此外，myriocin还可以在HFD诱导的NASH大鼠中恢复受损的肝自噬功能，这一点已在HepG2细胞中得到证实。在我们通过脂质组学概况筛选出的鞘脂物种中，与对照组和非NASH患者相比，在NASH患者中观察到神经酰胺显着增加，无论他们是否具有活性CHB。神经酰胺可能在NASH发病机理中的自噬功能中起重要的调节作用。因此，通过肉豆球蛋白对神经酰胺信号的阻断在NASH中可能具有治疗上的益处。注册ID：ChiCTR-DDT-13003983。注册数据：2013年5月13日，追溯注册。ChiCTR-DDT-13003983。注册数据：2013年5月13日，追溯注册。ChiCTR-DDT-13003983。注册数据：2013年5月13日，追溯注册。