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Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease

BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin...

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Autores principales: Iwaki, Michihiro, Kessoku, Takaomi, Tanaka, Kosuke, Ozaki, Anna, Kasai, Yuki, Kobayashi, Takashi, Nogami, Asako, Honda, Yasushi, Ogawa, Yuji, Imajo, Kento, Usuda, Haruki, Wada, Koichiro, Kobayashi, Noritoshi, Saito, Satoru, Nakajima, Atsushi, Yoneda, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10617934/
https://www.ncbi.nlm.nih.gov/pubmed/37902528
http://dx.doi.org/10.1097/HC9.0000000000000285
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author Iwaki, Michihiro
Kessoku, Takaomi
Tanaka, Kosuke
Ozaki, Anna
Kasai, Yuki
Kobayashi, Takashi
Nogami, Asako
Honda, Yasushi
Ogawa, Yuji
Imajo, Kento
Usuda, Haruki
Wada, Koichiro
Kobayashi, Noritoshi
Saito, Satoru
Nakajima, Atsushi
Yoneda, Masato
author_facet Iwaki, Michihiro
Kessoku, Takaomi
Tanaka, Kosuke
Ozaki, Anna
Kasai, Yuki
Kobayashi, Takashi
Nogami, Asako
Honda, Yasushi
Ogawa, Yuji
Imajo, Kento
Usuda, Haruki
Wada, Koichiro
Kobayashi, Noritoshi
Saito, Satoru
Nakajima, Atsushi
Yoneda, Masato
author_sort Iwaki, Michihiro
collection PubMed
description BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.
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spelling pubmed-106179342023-11-01 Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease Iwaki, Michihiro Kessoku, Takaomi Tanaka, Kosuke Ozaki, Anna Kasai, Yuki Kobayashi, Takashi Nogami, Asako Honda, Yasushi Ogawa, Yuji Imajo, Kento Usuda, Haruki Wada, Koichiro Kobayashi, Noritoshi Saito, Satoru Nakajima, Atsushi Yoneda, Masato Hepatol Commun Original Article BACKGROUND: Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. METHODS: Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). RESULTS: We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. CONCLUSIONS: Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH. Lippincott Williams & Wilkins 2023-10-31 /pmc/articles/PMC10617934/ /pubmed/37902528 http://dx.doi.org/10.1097/HC9.0000000000000285 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/) (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Original Article
Iwaki, Michihiro
Kessoku, Takaomi
Tanaka, Kosuke
Ozaki, Anna
Kasai, Yuki
Kobayashi, Takashi
Nogami, Asako
Honda, Yasushi
Ogawa, Yuji
Imajo, Kento
Usuda, Haruki
Wada, Koichiro
Kobayashi, Noritoshi
Saito, Satoru
Nakajima, Atsushi
Yoneda, Masato
Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
title Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
title_full Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
title_fullStr Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
title_full_unstemmed Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
title_short Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
title_sort combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10617934/
https://www.ncbi.nlm.nih.gov/pubmed/37902528
http://dx.doi.org/10.1097/HC9.0000000000000285
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