Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression
Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppresse...
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Elsevier
2025-03-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227525000173 |
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| author | Genta Kakiyama Nanah Bai-Kamara Daniel Rodriguez-Agudo Hajime Takei Kei Minowa Michael Fuchs Sudha Biddinger Jolene J. Windle Mark A. Subler Tsuyoshi Murai Mitsuyoshi Suzuki Hiroshi Nittono Arun Sanyal William M. Pandak |
| author_facet | Genta Kakiyama Nanah Bai-Kamara Daniel Rodriguez-Agudo Hajime Takei Kei Minowa Michael Fuchs Sudha Biddinger Jolene J. Windle Mark A. Subler Tsuyoshi Murai Mitsuyoshi Suzuki Hiroshi Nittono Arun Sanyal William M. Pandak |
| author_sort | Genta Kakiyama |
| collection | DOAJ |
| description | Effect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their WT counterparts, WD-fed CYP7B1hep.tg mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1hep.tg mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation, and immune system including retinol metabolism, arachidonic acid metabolism, and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1hep.tg mouse liver accumulated 26HC and 25HC in response to WD. These data strongly suggested that these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a “proof-of-concept” that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression. |
| format | Article |
| id | doaj-art-679960bfa4bf47eea4a4f8ef5ca5c746 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj-art-679960bfa4bf47eea4a4f8ef5ca5c7462025-08-20T03:42:18ZengElsevierJournal of Lipid Research0022-22752025-03-0166310075710.1016/j.jlr.2025.100757Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progressionGenta Kakiyama0Nanah Bai-Kamara1Daniel Rodriguez-Agudo2Hajime Takei3Kei Minowa4Michael Fuchs5Sudha Biddinger6Jolene J. Windle7Mark A. Subler8Tsuyoshi Murai9Mitsuyoshi Suzuki10Hiroshi Nittono11Arun Sanyal12William M. Pandak13Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USA; For correspondence: Genta KakiyamaResearch Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USADepartment of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USAJunshin Clinic Bile Acid Institute, Meguro-ku, Tokyo, JapanDepartment of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USA; Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, JapanDepartment of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USADivision of Endocrinology, Boston Children's Hospital, Harvard Medical School, MA, USADepartment of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond VA, USADepartment of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond VA, USASchool of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari, Hokkaido, JapanDepartment of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, JapanJunshin Clinic Bile Acid Institute, Meguro-ku, Tokyo, JapanDepartment of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University School of Medicine, Richmond, VA, USADepartment of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Research Services, Central Virginia Veterans Affairs Health Care System, Richmond, VA, USAEffect of liver specific oxysterol 7α-hydroxylase (CYP7B1) overexpression on the Western diet (WD)-induced metabolic dysfunction-associated steatotic liver disease (MASLD) progression was studied in mice. Among various hepatic genes impacted during MASLD development, CYP7B1 is consistently suppressed in multiple MASLD mouse models and in human MASLD cohorts. CYP7B1 enzyme suppression leads to accumulations of bioactive oxysterols such as (25R)26-hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). We challenged liver specific CYP7B1 transgenic (CYP7B1hep.tg) overexpressing mice with ad libitum WD feeding. Unlike their WT counterparts, WD-fed CYP7B1hep.tg mice developed no significant hepatotoxicity as evidenced by liver histology, lipid quantifications, and serum biomarker analyses. Hepatic 26HC and 25HC levels were maintained at the basal levels. The comparative gene expression/lipidomic analyses between WT and CYP7B1hep.tg mice revealed that chronically accumulated 26HC initiates LXR/PPAR-mediated hepatic fatty acid uptake and lipogenesis which surpasses fatty acid metabolism and export; compromising metabolic functions. In addition, major pathways related to oxidative stress, inflammation, and immune system including retinol metabolism, arachidonic acid metabolism, and linoleic acid metabolism were significantly impacted in the WD-fed WT mice. All pathways were unaltered in CYP7B1hep.tg mice liver. Furthermore, the nucleus of WT mouse liver but not of CYP7B1hep.tg mouse liver accumulated 26HC and 25HC in response to WD. These data strongly suggested that these two oxysterols are specifically important in nuclear transcriptional regulation for the described cytotoxic pathways. In conclusion, this study represents a “proof-of-concept” that maintaining normal mitochondrial cholesterol metabolism with hepatic CYP7B1 expression prevents oxysterol-driven liver toxicity; thus attenuating MASLD progression.http://www.sciencedirect.com/science/article/pii/S0022227525000173CD36cholesterolinflammationliverlipotoxicityoxysterol |
| spellingShingle | Genta Kakiyama Nanah Bai-Kamara Daniel Rodriguez-Agudo Hajime Takei Kei Minowa Michael Fuchs Sudha Biddinger Jolene J. Windle Mark A. Subler Tsuyoshi Murai Mitsuyoshi Suzuki Hiroshi Nittono Arun Sanyal William M. Pandak Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression Journal of Lipid Research CD36 cholesterol inflammation liver lipotoxicity oxysterol |
| title | Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression |
| title_full | Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression |
| title_fullStr | Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression |
| title_full_unstemmed | Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression |
| title_short | Liver specific transgenic expression of CYP7B1 attenuates early western diet-induced MASLD progression |
| title_sort | liver specific transgenic expression of cyp7b1 attenuates early western diet induced masld progression |
| topic | CD36 cholesterol inflammation liver lipotoxicity oxysterol |
| url | http://www.sciencedirect.com/science/article/pii/S0022227525000173 |
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