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Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease

CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Di...

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Autores principales: Minowa, Kei, Rodriguez-Agudo, Daniel, Suzuki, Mitsuyoshi, Muto, Yamato, Hirai, Saeko, Wang, Yaping, Su, Lianyong, Zhou, Huiping, Chen, Qun, Lesnefsky, Edward J., Mitamura, Kuniko, Ikegawa, Shigeo, Takei, Hajime, Nittono, Hiroshi, Fuchs, Michael, Pandak, William M., Kakiyama, Genta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182330/
https://www.ncbi.nlm.nih.gov/pubmed/36966904
http://dx.doi.org/10.1016/j.jlr.2023.100363
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author Minowa, Kei
Rodriguez-Agudo, Daniel
Suzuki, Mitsuyoshi
Muto, Yamato
Hirai, Saeko
Wang, Yaping
Su, Lianyong
Zhou, Huiping
Chen, Qun
Lesnefsky, Edward J.
Mitamura, Kuniko
Ikegawa, Shigeo
Takei, Hajime
Nittono, Hiroshi
Fuchs, Michael
Pandak, William M.
Kakiyama, Genta
author_facet Minowa, Kei
Rodriguez-Agudo, Daniel
Suzuki, Mitsuyoshi
Muto, Yamato
Hirai, Saeko
Wang, Yaping
Su, Lianyong
Zhou, Huiping
Chen, Qun
Lesnefsky, Edward J.
Mitamura, Kuniko
Ikegawa, Shigeo
Takei, Hajime
Nittono, Hiroshi
Fuchs, Michael
Pandak, William M.
Kakiyama, Genta
author_sort Minowa, Kei
collection PubMed
description CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1(−/−) mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1(−/−) mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1(−/−) mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1(−/−) mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.
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spelling pubmed-101823302023-05-14 Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease Minowa, Kei Rodriguez-Agudo, Daniel Suzuki, Mitsuyoshi Muto, Yamato Hirai, Saeko Wang, Yaping Su, Lianyong Zhou, Huiping Chen, Qun Lesnefsky, Edward J. Mitamura, Kuniko Ikegawa, Shigeo Takei, Hajime Nittono, Hiroshi Fuchs, Michael Pandak, William M. Kakiyama, Genta J Lipid Res Research Article CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1(−/−) mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1(−/−) mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1(−/−) mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1(−/−) mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease. American Society for Biochemistry and Molecular Biology 2023-03-24 /pmc/articles/PMC10182330/ /pubmed/36966904 http://dx.doi.org/10.1016/j.jlr.2023.100363 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Minowa, Kei
Rodriguez-Agudo, Daniel
Suzuki, Mitsuyoshi
Muto, Yamato
Hirai, Saeko
Wang, Yaping
Su, Lianyong
Zhou, Huiping
Chen, Qun
Lesnefsky, Edward J.
Mitamura, Kuniko
Ikegawa, Shigeo
Takei, Hajime
Nittono, Hiroshi
Fuchs, Michael
Pandak, William M.
Kakiyama, Genta
Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
title Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
title_full Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
title_fullStr Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
title_full_unstemmed Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
title_short Insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
title_sort insulin dysregulation drives mitochondrial cholesterol metabolite accumulation: initiating hepatic toxicity in nonalcoholic fatty liver disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10182330/
https://www.ncbi.nlm.nih.gov/pubmed/36966904
http://dx.doi.org/10.1016/j.jlr.2023.100363
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