• Rui-Xu Yang, Qin Pan, Xiao-Lin Liu, Da Zhou, Feng-Zhi Xin, Ze-Hua Zhao, Rui-Nan Zhang, Jing Zeng, Liang Qiao, Chun-Xiu Hu, Guo-Wang Xu, and Jian-Gao Fan.
• Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
• Lipids Health Dis. 2019 Oct 21; 18 (1): 179.

BackgroundCeramide 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.MethodsSprague 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).ResultsMyriocin 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.ConclusionsCeramide 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.Trial RegistrationRegistration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.

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