Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition
NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remai...
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Language: | English |
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Elsevier
2020-12-01
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Series: | Journal of Lipid Research |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520600244 |
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doaj-f22dc345203d48c1bae1f66f709fdca2 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Genta Kakiyama Dalila Marques Rebecca Martin Hajime Takei Daniel Rodriguez-Agudo Sandra A. LaSalle Taishi Hashiguchi Xiaoying Liu Richard Green Sandra Erickson Gregorio Gil Michael Fuchs Mitsuyoshi Suzuki Tsuyoshi Murai Hiroshi Nittono Phillip B. Hylemon Huiping Zhou William M. Pandak |
spellingShingle |
Genta Kakiyama Dalila Marques Rebecca Martin Hajime Takei Daniel Rodriguez-Agudo Sandra A. LaSalle Taishi Hashiguchi Xiaoying Liu Richard Green Sandra Erickson Gregorio Gil Michael Fuchs Mitsuyoshi Suzuki Tsuyoshi Murai Hiroshi Nittono Phillip B. Hylemon Huiping Zhou William M. Pandak Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition Journal of Lipid Research cholesterol toxicity oxysterol 7α-hydroxylase inflammation liver injury nonalcoholic fatty liver disease nonalcoholic steatohepatitis |
author_facet |
Genta Kakiyama Dalila Marques Rebecca Martin Hajime Takei Daniel Rodriguez-Agudo Sandra A. LaSalle Taishi Hashiguchi Xiaoying Liu Richard Green Sandra Erickson Gregorio Gil Michael Fuchs Mitsuyoshi Suzuki Tsuyoshi Murai Hiroshi Nittono Phillip B. Hylemon Huiping Zhou William M. Pandak |
author_sort |
Genta Kakiyama |
title |
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition |
title_short |
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition |
title_full |
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition |
title_fullStr |
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition |
title_full_unstemmed |
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition |
title_sort |
insulin resistance dysregulates cyp7b1 leading to oxysterol accumulation: a pathway for nafl to nash transition |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2020-12-01 |
description |
NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the “acidic/alternative” pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD. |
topic |
cholesterol toxicity oxysterol 7α-hydroxylase inflammation liver injury nonalcoholic fatty liver disease nonalcoholic steatohepatitis |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520600244 |
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doaj-f22dc345203d48c1bae1f66f709fdca22021-04-29T04:39:26ZengElsevierJournal of Lipid Research0022-22752020-12-01611216291644Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transitionGenta Kakiyama0Dalila Marques1Rebecca Martin2Hajime Takei3Daniel Rodriguez-Agudo4Sandra A. LaSalle5Taishi Hashiguchi6Xiaoying Liu7Richard Green8Sandra Erickson9Gregorio Gil10Michael Fuchs11Mitsuyoshi Suzuki12Tsuyoshi Murai13Hiroshi Nittono14Phillip B. Hylemon15Huiping Zhou16William M. Pandak17Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA; For correspondence: Genta Kakiyama; For correspondence: Genta KakiyamaDepartment of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USADepartment of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USAJunshin Clinic Bile Acid Institute, Tokyo, JapanDepartment of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USADepartment of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USASMC Laboratories Inc., Tokyo, JapanDepartment of Medicine, Northwestern University, Chicago, IL, USADepartment of Medicine, Northwestern University, Chicago, IL, USASchool of Medicine, University of California, San Francisco, San Francisco, CA, USADepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USADepartment of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USADepartment of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, JapanSchool of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, JapanJunshin Clinic Bile Acid Institute, Tokyo, JapanDepartment of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USADepartment of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USADepartment of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USANAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the “acidic/alternative” pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.http://www.sciencedirect.com/science/article/pii/S0022227520600244cholesterol toxicityoxysterol 7α-hydroxylaseinflammationliver injurynonalcoholic fatty liver diseasenonalcoholic steatohepatitis |