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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.
Afiliação
  • Minowa K; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Rodriguez-Agudo D; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
  • Suzuki M; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Muto Y; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Hirai S; Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
  • Wang Y; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
  • Su L; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
  • Zhou H; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
  • Chen Q; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
  • Lesnefsky EJ; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
  • Mitamura K; Department of Pharmaceutical Sciences, Kindai University, Osaka, Japan.
  • Ikegawa S; Division of Research and Development, Genmaikoso Co. Ltd., Sapporo, Hokkaido, Japan.
  • Takei H; Junshin Clinic Bile Acid Institute, Tokyo, Japan.
  • Nittono H; Junshin Clinic Bile Acid Institute, Tokyo, Japan.
  • Fuchs M; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA.
  • Pandak WM; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
  • Kakiyama G; Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Healthcare System, Richmond, VA, USA. Electronic address: genta.kakiyama@vcuhealth.org.
J Lipid Res ; 64(5): 100363, 2023 05.
Article em En | MEDLINE | ID: mdl-36966904
CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3ß-hydroxy-5-cholesten-(25R)26-oic acid (3ßHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3ßHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3ßHCA 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/3ßHCA 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/3ßHCA 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/3ßHCA accumulation. The results suggest 26HC/3ßHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3ßHCA 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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Hepatopatia Gordurosa não Alcoólica Limite: Animals / Humans Idioma: En Revista: J Lipid Res Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Hepatopatia Gordurosa não Alcoólica Limite: Animals / Humans Idioma: En Revista: J Lipid Res Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Japão