Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition
Autor: | Rebecca K. Martin, Mitsuyoshi Suzuki, Sandra A. LaSalle, Daniel Rodriguez-Agudo, Phillip B. Hylemon, Dalila Marques, Michael Fuchs, Hiroshi Nittono, Genta Kakiyama, Tsuyoshi Murai, William M. Pandak, Hajime Takei, Taishi Hashiguchi, Gregorio Gil, Huiping Zhou, Richard M. Green, Sandra K. Erickson, Xiaoying Liu |
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Rok vydání: | 2020 |
Předmět: |
nonalcoholic fatty liver disease
0301 basic medicine Oxysterol CYP7B1 Cytochrome P450 Family 7 QD415-436 030204 cardiovascular system & hematology Bioinformatics Biochemistry 03 medical and health sciences Mice 0302 clinical medicine Endocrinology Insulin resistance Downregulation and upregulation Non-alcoholic Fatty Liver Disease Diabetes mellitus Nonalcoholic fatty liver disease medicine Animals Humans nonalcoholic steatohepatitis Research Articles business.industry Steroidogenic acute regulatory protein Fatty liver Cell Biology Oxysterols oxysterol 7α-hydroxylase medicine.disease digestive system diseases 030104 developmental biology Liver inflammation Steroid Hydroxylases Hepatocytes cholesterol toxicity Insulin Resistance business liver injury |
Zdroj: | J Lipid Res Journal of Lipid Research, Vol 61, Iss 12, Pp 1629-1644 (2020) |
ISSN: | 1539-7262 |
Popis: | 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. |
Databáze: | OpenAIRE |
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