Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent...

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Autores principales:	Jingxin Liu, Tian Zhang, Jianzhong Zhu, Shuangchen Ruan, Rongsong Li, Bing Guo, Ligen Lin
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Honokiol Hepatocytes Lipid accumulation Lipophagy SIRT3 Lipolysis Other systems of medicine RZ201-999
Acceso en línea:	https://doaj.org/article/1e2622ed8c2f47cb819d9d30e93fa0e3
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spelling	oai:doaj.org-article:1e2622ed8c2f47cb819d9d30e93fa0e32021-11-14T12:10:23ZHonokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy10.1186/s13020-021-00528-w1749-8546https://doaj.org/article/1e2622ed8c2f47cb819d9d30e93fa0e32021-11-01T00:00:00Zhttps://doi.org/10.1186/s13020-021-00528-whttps://doaj.org/toc/1749-8546Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, modulates the activities of several substrates involving in autophagy and energy metabolism. Honokiol (HK) is a natural lignan from the plants of Magnolia genus that exhibits potent liver protective property. Methods AML12 was challenged with 500 μM palmitic acid and 250 μM oleic acid mixture solution to induce lipotoxicity. C57BL/6J mice were fed with a choline-deficient high fat diet (CDHFD) to generate liver steatosis. The expression of autophagy-related and AMP-activated protein kinase (AMPK) pathway proteins was evaluated by Western blotting and immunofluorescence staining. Intracellular lipid accumulation was validated by Nile red staining. Molecular docking analysis was performed on AutoDock 4.2. Results HK (5 and 10 μM) was found to attenuate lipid accumulation through promoting SIRT3-AMPK-mediated autophagy, mainly on lipid droplets. HK had hydrophobic interaction with amino acid residues (PHE294, GLU323 and VAL324) and NAD+. Moreover, HK improved mitochondrial function to enhance lipolysis, through decreasing the acetylated long-chain acyl-CoA dehydrogenase level. In CDHFD-fed mice, HK (2.5 and 10 mg/Kg) treatment obviously prevented lipid accumulation in the liver. And co-treatment of the AMPK inhibitor, Compound C, almost abolished the above changes. Conclusions These results suggest that HK could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK-lipophagy axis, which might be a potential therapeutic agent against NAFLD.Jingxin LiuTian ZhangJianzhong ZhuShuangchen RuanRongsong LiBing GuoLigen LinBMCarticleHonokiolHepatocytesLipid accumulationLipophagySIRT3LipolysisOther systems of medicineRZ201-999ENChinese Medicine, Vol 16, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Honokiol Hepatocytes Lipid accumulation Lipophagy SIRT3 Lipolysis Other systems of medicine RZ201-999
spellingShingle	Honokiol Hepatocytes Lipid accumulation Lipophagy SIRT3 Lipolysis Other systems of medicine RZ201-999 Jingxin Liu Tian Zhang Jianzhong Zhu Shuangchen Ruan Rongsong Li Bing Guo Ligen Lin Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy
description	Abstract Background Non-alcoholic fatty liver disease (NAFLD) is characterized by ectopic accumulation of triglycerides in the liver. Emerging evidence has demonstrated that lipophagy regulates lipid mobilization and energy homeostasis in the liver. Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, modulates the activities of several substrates involving in autophagy and energy metabolism. Honokiol (HK) is a natural lignan from the plants of Magnolia genus that exhibits potent liver protective property. Methods AML12 was challenged with 500 μM palmitic acid and 250 μM oleic acid mixture solution to induce lipotoxicity. C57BL/6J mice were fed with a choline-deficient high fat diet (CDHFD) to generate liver steatosis. The expression of autophagy-related and AMP-activated protein kinase (AMPK) pathway proteins was evaluated by Western blotting and immunofluorescence staining. Intracellular lipid accumulation was validated by Nile red staining. Molecular docking analysis was performed on AutoDock 4.2. Results HK (5 and 10 μM) was found to attenuate lipid accumulation through promoting SIRT3-AMPK-mediated autophagy, mainly on lipid droplets. HK had hydrophobic interaction with amino acid residues (PHE294, GLU323 and VAL324) and NAD+. Moreover, HK improved mitochondrial function to enhance lipolysis, through decreasing the acetylated long-chain acyl-CoA dehydrogenase level. In CDHFD-fed mice, HK (2.5 and 10 mg/Kg) treatment obviously prevented lipid accumulation in the liver. And co-treatment of the AMPK inhibitor, Compound C, almost abolished the above changes. Conclusions These results suggest that HK could ameliorate lipotoxicity in hepatocytes by activating SIRT3-AMPK-lipophagy axis, which might be a potential therapeutic agent against NAFLD.
format	article
author	Jingxin Liu Tian Zhang Jianzhong Zhu Shuangchen Ruan Rongsong Li Bing Guo Ligen Lin
author_facet	Jingxin Liu Tian Zhang Jianzhong Zhu Shuangchen Ruan Rongsong Li Bing Guo Ligen Lin
author_sort	Jingxin Liu
title	Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy
title_short	Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy
title_full	Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy
title_fullStr	Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy
title_full_unstemmed	Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy
title_sort	honokiol attenuates lipotoxicity in hepatocytes via activating sirt3-ampk mediated lipophagy
publisher	BMC
publishDate	2021
url	https://doaj.org/article/1e2622ed8c2f47cb819d9d30e93fa0e3
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_version_	1718429392848289792

Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK mediated lipophagy

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