Background 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. Methods 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). Results 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. Conclusions 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. Trial registration Registration ID: ChiCTR-DDT-13003983 . Data of registration: 13 May, 2013, retrospectively registered.
【저자키워드】 autophagy, Ceramides, High fat diet, Non-alcoholic fatty liver disease, 【초록키워드】 Treatment, Pathogenesis, body weight, animal model, autophagy, metabolism, Regulatory, Registration, Adults, qPCR, Patient, Control, Fatty liver, mechanisms, disease, change, liver, dyslipidemia, Fatty acid, sphingolipid, administration, Chronic Hepatitis B, NAFLD, Liver Biopsy, chronic hepatitis, fatty liver disease, oral administration, serum transaminases, alternate days, ceramide, Nonalcoholic Fatty Liver Disease, PPARα, subject, RATs, profiles, three groups, Registered, pathogenic, blockade, expression pattern, steatosis, Acox-2, active CHB, autophagy function, autophagy markers, ballooning, Cpt-1α, Fabp1, fatty acid metabolism, HepG2 cells, HFD-induced NASH, Lipid accumulation, liver biopsy-proven patients, Liver histology, liver pathology, lobular inflammation, myriocin, NASH, NASH patients, non-NASH patients, qPCR analysis, de novo synthesis, significantly increased, Result, analyzed, significantly, healthy, elevated, screened, restored, were measured, reversed, incubated, autophagy marker, ceramide signaling, CHB, fatty, hepatic autophagy function, HepG2 cell, liver biopsy-proven patient, NASH patient, nonalcoholic fatty liver, randomly divided, serum transaminase, 【제목키워드】 Regulation, steatohepatitis,