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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BMC
2019-10-01
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Series: | Lipids in Health and Disease |
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Online Access: | http://link.springer.com/article/10.1186/s12944-019-1118-0 |
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doaj-b4bece4b1dce400b8c866aefb6ebc069 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
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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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 |