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Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)

Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in...

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Autores principales: Tai, Tsai-Sung, Tien, Ni, Shen, Hsin-Yi, Chu, Fang-Yi, Wang, Charles C. N., Lu, Chieh-Hsiang, Yu, Hui-I, Kung, Fang-Ping, Chuang, Hsiang-Hsun, Lee, Ying-Ray, Chang, Hsiao-Yun, Lim, Yun-Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959160/
https://www.ncbi.nlm.nih.gov/pubmed/31976003
http://dx.doi.org/10.1155/2019/9401648
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author Tai, Tsai-Sung
Tien, Ni
Shen, Hsin-Yi
Chu, Fang-Yi
Wang, Charles C. N.
Lu, Chieh-Hsiang
Yu, Hui-I
Kung, Fang-Ping
Chuang, Hsiang-Hsun
Lee, Ying-Ray
Chang, Hsiao-Yun
Lim, Yun-Ping
author_facet Tai, Tsai-Sung
Tien, Ni
Shen, Hsin-Yi
Chu, Fang-Yi
Wang, Charles C. N.
Lu, Chieh-Hsiang
Yu, Hui-I
Kung, Fang-Ping
Chuang, Hsiang-Hsun
Lee, Ying-Ray
Chang, Hsiao-Yun
Lim, Yun-Ping
author_sort Tai, Tsai-Sung
collection PubMed
description Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in many dietary plants and has a wide range of beneficial effects on metabolism. The mechanism underlying sesamin action especially on the regulation of LXR remains elusive. Reporter assays, mRNA and protein expression, and in silico modeling were used to identify sesamin as an antagonist of LXRα. Sesamin was applied to the hepatic HepaRG and intestinal LS174T cells and showed that it markedly ameliorated lipid accumulation in the HepaRG cells, by reducing LXRα transactivation, inhibiting the expression of downstream target genes. This effect was associated with the stimulation of AMP-activated protein kinase (AMPK) signaling pathway, followed by decreased T0901317-LXRα-induced expression of SREBP-1c and its downstream target genes. Mechanistically, sesamin reduced the recruitment of SRC-1 but enhanced that of SMILE to the SREBP-1c promoter region under T0901317 treatment. It regulated the transcriptional control exerted by LXRα by influencing its interaction with coregulators and thus decreased mRNA and protein levels of genes downstream of LXRα and reduced lipid accumulation in hepatic cells. Additionally, sesamin reduced valproate- and rifampin-induced LXRα and pregnane X receptor (PXR) transactivation. This was associated with reduced expression of target genes and decreased lipid accumulation. Thus, sesamin is an antagonist of LXRα and PXR and suggests that it may alleviate drug-induced lipogenesis via the suppression of LXRα and PXR signaling.
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spelling pubmed-69591602020-01-23 Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR) Tai, Tsai-Sung Tien, Ni Shen, Hsin-Yi Chu, Fang-Yi Wang, Charles C. N. Lu, Chieh-Hsiang Yu, Hui-I Kung, Fang-Ping Chuang, Hsiang-Hsun Lee, Ying-Ray Chang, Hsiao-Yun Lim, Yun-Ping Evid Based Complement Alternat Med Research Article Liver X receptor (LXR) is a nuclear receptor that regulates various biological processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver disease (NAFLD). Sesamin is a naturally occurring lignan in many dietary plants and has a wide range of beneficial effects on metabolism. The mechanism underlying sesamin action especially on the regulation of LXR remains elusive. Reporter assays, mRNA and protein expression, and in silico modeling were used to identify sesamin as an antagonist of LXRα. Sesamin was applied to the hepatic HepaRG and intestinal LS174T cells and showed that it markedly ameliorated lipid accumulation in the HepaRG cells, by reducing LXRα transactivation, inhibiting the expression of downstream target genes. This effect was associated with the stimulation of AMP-activated protein kinase (AMPK) signaling pathway, followed by decreased T0901317-LXRα-induced expression of SREBP-1c and its downstream target genes. Mechanistically, sesamin reduced the recruitment of SRC-1 but enhanced that of SMILE to the SREBP-1c promoter region under T0901317 treatment. It regulated the transcriptional control exerted by LXRα by influencing its interaction with coregulators and thus decreased mRNA and protein levels of genes downstream of LXRα and reduced lipid accumulation in hepatic cells. Additionally, sesamin reduced valproate- and rifampin-induced LXRα and pregnane X receptor (PXR) transactivation. This was associated with reduced expression of target genes and decreased lipid accumulation. Thus, sesamin is an antagonist of LXRα and PXR and suggests that it may alleviate drug-induced lipogenesis via the suppression of LXRα and PXR signaling. Hindawi 2019-11-25 /pmc/articles/PMC6959160/ /pubmed/31976003 http://dx.doi.org/10.1155/2019/9401648 Text en Copyright © 2019 Tsai-Sung Tai et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Tai, Tsai-Sung
Tien, Ni
Shen, Hsin-Yi
Chu, Fang-Yi
Wang, Charles C. N.
Lu, Chieh-Hsiang
Yu, Hui-I
Kung, Fang-Ping
Chuang, Hsiang-Hsun
Lee, Ying-Ray
Chang, Hsiao-Yun
Lim, Yun-Ping
Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)
title Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)
title_full Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)
title_fullStr Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)
title_full_unstemmed Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)
title_short Sesamin, a Naturally Occurring Lignan, Inhibits Ligand-Induced Lipogenesis through Interaction with Liver X Receptor Alpha (LXRα) and Pregnane X Receptor (PXR)
title_sort sesamin, a naturally occurring lignan, inhibits ligand-induced lipogenesis through interaction with liver x receptor alpha (lxrα) and pregnane x receptor (pxr)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959160/
https://www.ncbi.nlm.nih.gov/pubmed/31976003
http://dx.doi.org/10.1155/2019/9401648
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