Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis

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 inhibitio...

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Main Authors: 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, Jian-Gao Fan
Format: Article
Language:English
Published: BMC 2019-10-01
Series:Lipids in Health and Disease
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12944-019-1118-0
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language English
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author 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
Jian-Gao Fan
spellingShingle 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
Jian-Gao Fan
Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
Lipids in Health and Disease
Ceramides
Autophagy
High fat diet
Non-alcoholic fatty liver disease
author_facet 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
Jian-Gao Fan
author_sort Rui-Xu Yang
title Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
title_short Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
title_full Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
title_fullStr Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
title_full_unstemmed Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
title_sort therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitis
publisher BMC
series Lipids in Health and Disease
issn 1476-511X
publishDate 2019-10-01
description 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.
topic Ceramides
Autophagy
High fat diet
Non-alcoholic fatty liver disease
url http://link.springer.com/article/10.1186/s12944-019-1118-0
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spelling doaj-b4bece4b1dce400b8c866aefb6ebc0692020-11-25T03:37:09ZengBMCLipids in Health and Disease1476-511X2019-10-0118111110.1186/s12944-019-1118-0Therapeutic effect and autophagy regulation of myriocin in nonalcoholic steatohepatitisRui-Xu Yang0Qin Pan1Xiao-Lin Liu2Da Zhou3Feng-Zhi Xin4Ze-Hua Zhao5Rui-Nan Zhang6Jing Zeng7Liang Qiao8Chun-Xiu Hu9Guo-Wang Xu10Jian-Gao Fan11Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineStorr Liver Centre, Westmead Institute for Medical Research, the University of Sydney at Westmead HospitalCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of SciencesCAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of SciencesCenter for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of MedicineAbstract 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.http://link.springer.com/article/10.1186/s12944-019-1118-0CeramidesAutophagyHigh fat dietNon-alcoholic fatty liver disease