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Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression

Macrophage inhibitory cytokine 1 (MIC-1), which is overproduced in various human cancers and associated with cachexia, acts on the hypothalamus to suppress appetite and reduce body weight. We investigated the mechanisms through which MIC-1 affects bile acid metabolism and gallstone formation, which...

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Autores principales: Kim, Min Hee, Lee, Eun-Ji, Kim, Su-Jeong, Jung, Yun-Jae, Park, Woo-Jae, Park, Inkeun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10263326/
https://www.ncbi.nlm.nih.gov/pubmed/37310967
http://dx.doi.org/10.1371/journal.pone.0287146
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author Kim, Min Hee
Lee, Eun-Ji
Kim, Su-Jeong
Jung, Yun-Jae
Park, Woo-Jae
Park, Inkeun
author_facet Kim, Min Hee
Lee, Eun-Ji
Kim, Su-Jeong
Jung, Yun-Jae
Park, Woo-Jae
Park, Inkeun
author_sort Kim, Min Hee
collection PubMed
description Macrophage inhibitory cytokine 1 (MIC-1), which is overproduced in various human cancers and associated with cachexia, acts on the hypothalamus to suppress appetite and reduce body weight. We investigated the mechanisms through which MIC-1 affects bile acid metabolism and gallstone formation, which are poorly understood. Over 6 weeks, male C57BL/6 mice fed either standard chow or a lithogenic diet were intraperitoneally injected with phosphate-buffered saline (PBS) or MIC-1 (200 μg/kg/week). Among lithogenic diet–fed mice, MIC-1 treatment resulted in increased gallstone formation compared with PBS treatment. Compared with PBS treatment, MIC-1 treatment decreased hepatic cholesterol and bile acid levels and reduced expression of HMG-CoA reductase (HMGCR), the master cholesterol metabolism regulator sterol regulatory element-binding protein 2, cholesterol 7α-hydroxylase (CYP7A1), mitochondrial sterol 27-hydroxylase, and oxysterol 7α-hydroxylase. Compared with PBS treatment, MIC-1 treatment had no effect on small heterodimer partner, farnesoid X receptor, or pregnane X receptor expression, and extracellular signal–related kinase and c-Jun N-terminal kinase phosphorylation decreased, suggesting that these factors do not contribute to the MIC-1–induced reduction in CYP7A1 expression. Compared with PBS treatment, MIC-1 treatment increased AMP-activated protein kinase (AMPK) phosphorylation. Treatment with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced CYP7A1 and HMGCR expression, whereas the AMPK inhibitor Compound C reversed MIC-1-induced reductions in CYP7A1 and HMGCR expression. Furthermore, in MIC-1-treated mice, total biliary cholesterol levels increased together with increased ATP-binding cassette subfamily G (ABCG)5 and ABCG8 expression. Compared with PBS treatment, MIC-1 treatment did not affect expression of liver X receptors α and β, liver receptor homolog 1, hepatocyte nuclear factor 4α, or NR1I3 (also known as constitutive androstane receptor), which are upstream of ABCG5/8; however, MIC-1 treatment increased ABCG5/8 expression and promoter activities. Our study indicates that MIC-1 influences gallstone formation by increasing AMPK phosphorylation, reducing CYP7A1 and HMGCR expression, and increasing ABCG5 and ABCG8 expression.
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spelling pubmed-102633262023-06-15 Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression Kim, Min Hee Lee, Eun-Ji Kim, Su-Jeong Jung, Yun-Jae Park, Woo-Jae Park, Inkeun PLoS One Research Article Macrophage inhibitory cytokine 1 (MIC-1), which is overproduced in various human cancers and associated with cachexia, acts on the hypothalamus to suppress appetite and reduce body weight. We investigated the mechanisms through which MIC-1 affects bile acid metabolism and gallstone formation, which are poorly understood. Over 6 weeks, male C57BL/6 mice fed either standard chow or a lithogenic diet were intraperitoneally injected with phosphate-buffered saline (PBS) or MIC-1 (200 μg/kg/week). Among lithogenic diet–fed mice, MIC-1 treatment resulted in increased gallstone formation compared with PBS treatment. Compared with PBS treatment, MIC-1 treatment decreased hepatic cholesterol and bile acid levels and reduced expression of HMG-CoA reductase (HMGCR), the master cholesterol metabolism regulator sterol regulatory element-binding protein 2, cholesterol 7α-hydroxylase (CYP7A1), mitochondrial sterol 27-hydroxylase, and oxysterol 7α-hydroxylase. Compared with PBS treatment, MIC-1 treatment had no effect on small heterodimer partner, farnesoid X receptor, or pregnane X receptor expression, and extracellular signal–related kinase and c-Jun N-terminal kinase phosphorylation decreased, suggesting that these factors do not contribute to the MIC-1–induced reduction in CYP7A1 expression. Compared with PBS treatment, MIC-1 treatment increased AMP-activated protein kinase (AMPK) phosphorylation. Treatment with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced CYP7A1 and HMGCR expression, whereas the AMPK inhibitor Compound C reversed MIC-1-induced reductions in CYP7A1 and HMGCR expression. Furthermore, in MIC-1-treated mice, total biliary cholesterol levels increased together with increased ATP-binding cassette subfamily G (ABCG)5 and ABCG8 expression. Compared with PBS treatment, MIC-1 treatment did not affect expression of liver X receptors α and β, liver receptor homolog 1, hepatocyte nuclear factor 4α, or NR1I3 (also known as constitutive androstane receptor), which are upstream of ABCG5/8; however, MIC-1 treatment increased ABCG5/8 expression and promoter activities. Our study indicates that MIC-1 influences gallstone formation by increasing AMPK phosphorylation, reducing CYP7A1 and HMGCR expression, and increasing ABCG5 and ABCG8 expression. Public Library of Science 2023-06-13 /pmc/articles/PMC10263326/ /pubmed/37310967 http://dx.doi.org/10.1371/journal.pone.0287146 Text en © 2023 Kim et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kim, Min Hee
Lee, Eun-Ji
Kim, Su-Jeong
Jung, Yun-Jae
Park, Woo-Jae
Park, Inkeun
Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression
title Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression
title_full Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression
title_fullStr Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression
title_full_unstemmed Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression
title_short Macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased ABCG5/ABCG8 expression
title_sort macrophage inhibitory cytokine-1 aggravates diet-induced gallstone formation via increased abcg5/abcg8 expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10263326/
https://www.ncbi.nlm.nih.gov/pubmed/37310967
http://dx.doi.org/10.1371/journal.pone.0287146
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