Cargando…

Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling

Objective: Mangiferin (MGF) is a natural xanthone, with regulation effect on lipid metabolism. However, the molecular mechanism remains unclear. We purposed after oral administration, MGF is converted to its active metabolite(s), which contributes to the effects on lipid metabolism. Methods: KK-A(y)...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Jian, Liu, Mengyang, Yu, Haiyang, Wang, Wei, Han, Lifeng, Chen, Qian, Ruan, Jingya, Wen, Shaoshi, Zhang, Yi, Wang, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850072/
https://www.ncbi.nlm.nih.gov/pubmed/29563875
http://dx.doi.org/10.3389/fphar.2018.00201
_version_ 1783306162883526656
author Li, Jian
Liu, Mengyang
Yu, Haiyang
Wang, Wei
Han, Lifeng
Chen, Qian
Ruan, Jingya
Wen, Shaoshi
Zhang, Yi
Wang, Tao
author_facet Li, Jian
Liu, Mengyang
Yu, Haiyang
Wang, Wei
Han, Lifeng
Chen, Qian
Ruan, Jingya
Wen, Shaoshi
Zhang, Yi
Wang, Tao
author_sort Li, Jian
collection PubMed
description Objective: Mangiferin (MGF) is a natural xanthone, with regulation effect on lipid metabolism. However, the molecular mechanism remains unclear. We purposed after oral administration, MGF is converted to its active metabolite(s), which contributes to the effects on lipid metabolism. Methods: KK-A(y) mice were used to validate the effects of MGF on lipid metabolic disorders. Liver biochemical indices and gene expressions were determined. MGF metabolites were isolated from MGF administrated rat urine. Mechanism studies were carried out using HepG2 cells treated by MGF and its metabolite with or without inhibitors or small interfering RNA (siRNA). Western blot and immunoprecipitation methods were used to determine the lipid metabolism related gene expression. AMP/ATP ratios were measured by HPLC. AMP-activated protein kinase (AMPK) activation were identified by homogeneous time resolved fluorescence (HTRF) assays. Results: MGF significantly decreased liver triglyceride and free fatty acid levels, increased sirtuin-1 (SIRT-1) and AMPK phosphorylation in KK-A(y) mice. HTRF studies indicated that MGF and its metabolites were not direct AMPK activators. Norathyriol, one of MGF’s metabolite, possess stronger regulating effect on hepatic lipid metabolism than MGF. The mechanism was mediated by activation of SIRT-1, liver kinase B1, and increasing the intracellular AMP level and AMP/ATP ratio, followed by AMPK phosphorylation, lead to increased phosphorylation level of sterol regulatory element-binding protein-1c. Conclusion: These results provided new insight into the molecular mechanisms of MGF in protecting against hepatic lipid metabolic disorders via regulating SIRT-1/AMPK pathway. Norathyriol showed potential therapeutic in treatment of non-alcoholic fatty liver disease.
format Online
Article
Text
id pubmed-5850072
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-58500722018-03-21 Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling Li, Jian Liu, Mengyang Yu, Haiyang Wang, Wei Han, Lifeng Chen, Qian Ruan, Jingya Wen, Shaoshi Zhang, Yi Wang, Tao Front Pharmacol Pharmacology Objective: Mangiferin (MGF) is a natural xanthone, with regulation effect on lipid metabolism. However, the molecular mechanism remains unclear. We purposed after oral administration, MGF is converted to its active metabolite(s), which contributes to the effects on lipid metabolism. Methods: KK-A(y) mice were used to validate the effects of MGF on lipid metabolic disorders. Liver biochemical indices and gene expressions were determined. MGF metabolites were isolated from MGF administrated rat urine. Mechanism studies were carried out using HepG2 cells treated by MGF and its metabolite with or without inhibitors or small interfering RNA (siRNA). Western blot and immunoprecipitation methods were used to determine the lipid metabolism related gene expression. AMP/ATP ratios were measured by HPLC. AMP-activated protein kinase (AMPK) activation were identified by homogeneous time resolved fluorescence (HTRF) assays. Results: MGF significantly decreased liver triglyceride and free fatty acid levels, increased sirtuin-1 (SIRT-1) and AMPK phosphorylation in KK-A(y) mice. HTRF studies indicated that MGF and its metabolites were not direct AMPK activators. Norathyriol, one of MGF’s metabolite, possess stronger regulating effect on hepatic lipid metabolism than MGF. The mechanism was mediated by activation of SIRT-1, liver kinase B1, and increasing the intracellular AMP level and AMP/ATP ratio, followed by AMPK phosphorylation, lead to increased phosphorylation level of sterol regulatory element-binding protein-1c. Conclusion: These results provided new insight into the molecular mechanisms of MGF in protecting against hepatic lipid metabolic disorders via regulating SIRT-1/AMPK pathway. Norathyriol showed potential therapeutic in treatment of non-alcoholic fatty liver disease. Frontiers Media S.A. 2018-03-07 /pmc/articles/PMC5850072/ /pubmed/29563875 http://dx.doi.org/10.3389/fphar.2018.00201 Text en Copyright © 2018 Li, Liu, Yu, Wang, Han, Chen, Ruan, Wen, Zhang and Wang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Jian
Liu, Mengyang
Yu, Haiyang
Wang, Wei
Han, Lifeng
Chen, Qian
Ruan, Jingya
Wen, Shaoshi
Zhang, Yi
Wang, Tao
Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling
title Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling
title_full Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling
title_fullStr Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling
title_full_unstemmed Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling
title_short Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling
title_sort mangiferin improves hepatic lipid metabolism mainly through its metabolite-norathyriol by modulating sirt-1/ampk/srebp-1c signaling
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850072/
https://www.ncbi.nlm.nih.gov/pubmed/29563875
http://dx.doi.org/10.3389/fphar.2018.00201
work_keys_str_mv AT lijian mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT liumengyang mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT yuhaiyang mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT wangwei mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT hanlifeng mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT chenqian mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT ruanjingya mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT wenshaoshi mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT zhangyi mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling
AT wangtao mangiferinimproveshepaticlipidmetabolismmainlythroughitsmetabolitenorathyriolbymodulatingsirt1ampksrebp1csignaling