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Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet

The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the u...

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Autores principales: Okushin, Kazuya, Tsutsumi, Takeya, Ikeuchi, Kazuhiko, Kado, Akira, Enooku, Kenichiro, Fujinaga, Hidetaka, Yamauchi, Naoko, Ushiku, Tetsuo, Moriya, Kyoji, Yotsuyanagi, Hiroshi, Koike, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423142/
https://www.ncbi.nlm.nih.gov/pubmed/32785220
http://dx.doi.org/10.1371/journal.pone.0234750
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author Okushin, Kazuya
Tsutsumi, Takeya
Ikeuchi, Kazuhiko
Kado, Akira
Enooku, Kenichiro
Fujinaga, Hidetaka
Yamauchi, Naoko
Ushiku, Tetsuo
Moriya, Kyoji
Yotsuyanagi, Hiroshi
Koike, Kazuhiko
author_facet Okushin, Kazuya
Tsutsumi, Takeya
Ikeuchi, Kazuhiko
Kado, Akira
Enooku, Kenichiro
Fujinaga, Hidetaka
Yamauchi, Naoko
Ushiku, Tetsuo
Moriya, Kyoji
Yotsuyanagi, Hiroshi
Koike, Kazuhiko
author_sort Okushin, Kazuya
collection PubMed
description The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the underlying mechanism, we analyzed Bsep heterozygous knock-out (Bsep(+/-) mice) and wild-type (WT) C57BL/6J mice fed a high-fat diet (HFD) (32.0% animal fat) or normal diet. We examined histological changes, levels of hepatic lipids and hepatic bile acids, and expression of genes related to bile acid and cholesterol metabolism. HFD-fed Bsep(+/-) mice exhibited milder hepatic steatosis and less weight gain, compared to HFD-fed WT mice. The concentrations of total bile acid, triglycerides, and cholesterols were reduced in the liver of HFD-fed Bsep(+/-) mice. Regarding hepatic bile acid metabolism, the expression levels of Farnesoid X receptor (Fxr) and Multidrug resistance-associated protein 2 were significantly upregulated in HFD-fed Bsep(+/-) mice, compared to HFD-fed WT mice. Furthermore, several alterations were observed in upstream cholesterol metabolism in the liver. The expression levels of bile acid metabolism-related genes were also altered in the intestine of HFD-fed Bsep(+/-) mice. In conclusion, HFD-fed Bsep(+/-) mice exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in both the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the involvement of BSEP in the pathogenesis of NASH will provide greater insight and facilitate the development of novel therapeutic modalities.
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spelling pubmed-74231422020-08-20 Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet Okushin, Kazuya Tsutsumi, Takeya Ikeuchi, Kazuhiko Kado, Akira Enooku, Kenichiro Fujinaga, Hidetaka Yamauchi, Naoko Ushiku, Tetsuo Moriya, Kyoji Yotsuyanagi, Hiroshi Koike, Kazuhiko PLoS One Research Article The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, including in Asian countries. We reported that the hepatic expression of bile salt export pump (BSEP) was downregulated in patients with NASH, suggesting that BSEP is involved in the pathogenesis of NASH. To identify the underlying mechanism, we analyzed Bsep heterozygous knock-out (Bsep(+/-) mice) and wild-type (WT) C57BL/6J mice fed a high-fat diet (HFD) (32.0% animal fat) or normal diet. We examined histological changes, levels of hepatic lipids and hepatic bile acids, and expression of genes related to bile acid and cholesterol metabolism. HFD-fed Bsep(+/-) mice exhibited milder hepatic steatosis and less weight gain, compared to HFD-fed WT mice. The concentrations of total bile acid, triglycerides, and cholesterols were reduced in the liver of HFD-fed Bsep(+/-) mice. Regarding hepatic bile acid metabolism, the expression levels of Farnesoid X receptor (Fxr) and Multidrug resistance-associated protein 2 were significantly upregulated in HFD-fed Bsep(+/-) mice, compared to HFD-fed WT mice. Furthermore, several alterations were observed in upstream cholesterol metabolism in the liver. The expression levels of bile acid metabolism-related genes were also altered in the intestine of HFD-fed Bsep(+/-) mice. In conclusion, HFD-fed Bsep(+/-) mice exhibited significant alterations of the expression levels of genes related to bile acid and lipid metabolism in both the liver and ileum, resulting in alleviated steatosis and less weight gain. These results suggest the importance of BSEP for maintenance of bile acid and cholesterol metabolism. Further investigations of the involvement of BSEP in the pathogenesis of NASH will provide greater insight and facilitate the development of novel therapeutic modalities. Public Library of Science 2020-08-12 /pmc/articles/PMC7423142/ /pubmed/32785220 http://dx.doi.org/10.1371/journal.pone.0234750 Text en © 2020 Okushin et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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
Okushin, Kazuya
Tsutsumi, Takeya
Ikeuchi, Kazuhiko
Kado, Akira
Enooku, Kenichiro
Fujinaga, Hidetaka
Yamauchi, Naoko
Ushiku, Tetsuo
Moriya, Kyoji
Yotsuyanagi, Hiroshi
Koike, Kazuhiko
Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
title Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
title_full Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
title_fullStr Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
title_full_unstemmed Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
title_short Heterozygous knockout of Bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
title_sort heterozygous knockout of bile salt export pump ameliorates liver steatosis in mice fed a high-fat diet
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423142/
https://www.ncbi.nlm.nih.gov/pubmed/32785220
http://dx.doi.org/10.1371/journal.pone.0234750
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