TY - JOUR
T1 - Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation
T2 - A pathway for NAFL to NASH transition
AU - Kakiyama, Genta
AU - Marques, Dalila
AU - Martin, Rebecca
AU - Takei, Hajime
AU - Rodriguez-Agudo, Daniel
AU - LaSalle, Sandra A.
AU - Hashiguchi, Taishi
AU - Liu, Xiaoying
AU - Green, Richard
AU - Erickson, Sandra
AU - Gil, Gregorio
AU - Fuchs, Michael
AU - Suzuki, Mitsuyoshi
AU - Murai, Tsuyoshi
AU - Nittono, Hiroshi
AU - Hylemon, Phillip B.
AU - Zhou, Huiping
AU - Pandak, William M.
N1 - Funding Information:
This work was supported by Gilead Sciences Liver Research Award 2016 to G.K. and Veterans Administration Veterans Affairs Merit Award I01 BX000197-07 to W.M.P. NIH-sponsored Liver Tissue Distribution Center at the University of Minnesota supplied presented human liver tissues used for analysis.
Publisher Copyright:
© 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Cholesterol toxicity
KW - Inflammation
KW - Liver injury
KW - Nonalcoholic fatty liver
KW - Nonalcoholic fatty liver disease
KW - Nonalcoholic steatohepatitis
KW - Oxysterol
KW - Oxysterol 7α- hydroxylase
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U2 - 10.1194/jlr.RA120000924
DO - 10.1194/jlr.RA120000924
M3 - Article
C2 - 33008924
AN - SCOPUS:85097004895
VL - 61
SP - 1629
EP - 1644
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 12
ER -
