Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis

Lipids in Health and Disease

Guo-Wang Xu¹  Chun-Xiu Hu¹  Ze-Hua Zhao²  Qin Pan²  Jian-Gao Fan²  Rui-Nan Zhang²  Feng-Zhi Xin²  Jing Zeng²  Rui-Xu Yang²  Xiao-Lin Liu²  Da Zhou²  Liang Qiao³ 

[1] CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences;Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine;Storr Liver Centre, Westmead Institute for Medical Research, the University of Sydney at Westmead Hospital;

关键词: Ceramides;    Autophagy;    High fat diet;    Non-alcoholic fatty liver disease;   

DOI  :  10.1186/s12944-019-1118-0

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown