Abstract
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.
Highlights
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
Inhibition of ceramide synthesis by myriocin attenuated high-fat diet (HFD) induced-Nonalcoholic steatohepatitis (NASH) in rats Rats fed HFD for 16 weeks demonstrated a significant increase in body weight as compared to the rats in the control group
Increased body weight in these rats was associated with widespread abnormalities in blood biochemistry, including a significant increase in the serum level of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Total cholesterol (TC), TG and Low density lipoprotein (LDL), and a significant decrease in the serum level of High density lipoprotein (HDL), as compared to the control group
Summary
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. We aimed to explore whether inhibition of ceramide signaling by myriocin is beneficial in animal model of NAFLD via regulating autophagy. Nonalcoholic steatohepatitis (NASH) is the severe form of NAFLD and if left untreated, can evolve into end stage liver diseases such as liver cirrhosis and hepatocellular carcinoma. Ceramides play important roles in multiple biological processes including cellular proliferation, differentiation, apoptosis, insulin resistance, oxidative stress and inflammation, all of which are known to be closely linked to the development of NAFLD [5,6,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
