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Abstract Details
Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition
Genta Kakiyama1, Dalila Marques2, Rebecca Martin3, Hajime Takei4, Daniel Rodriguez-Agudo2, Sandra A LaSalle5, Taishi Hashiguchi6, Xiaoying Liu7, Richard Green7, Sandra Erickson8, Gregorio Gil9, Michael Fuchs2, Mitsuyoshi Suzuki10, Tsuyoshi Murai11, Hiroshi Nittono4, Phillip B Hylemon12, Huiping Zhou12, William M Pandak13
Author information
1Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA. Electronic address: genta.kakiyama@vcuhealth.org.
2Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA.
3Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
4Junshin Clinic Bile Acid Institute, Tokyo, Japan.
5Department of Veterans Affairs, McGuire Veterans Administration Medical Center, Richmond, VA, USA.
6SMC Laboratories Inc., Tokyo, Japan.
7Department of Medicine, Northwestern University, Chicago, IL, USA.
8School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
9Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
10Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan.
11School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan.
12Department 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, USA.
13Department 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, USA.
Abstract
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.