首页|Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition

Insulin resistance dysregulates CYP7B1 leading to oxysterol accumulation: a pathway for NAFL to NASH transition

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  • NSTL
  • Elsevier
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 7 alpha -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.

cholesterol toxicityoxysterol 7 alpha-hydroxylaseinflammationliver injurynonalcoholic fatty liver diseasenonalcoholic steatohepatitisoxysterolnonalcoholic fatty liver

Liu, Xiaoying、Green, Richard、Erickson, Sandra、Gil, Gregorio、Fuchs, Michael、Suzuki, Mitsuyoshi、Murai, Tsuyoshi、Nittono, Hiroshi、Hylemon, Phillip B.、Zhou, Huiping、Pandak, William M.、Kakiyama, Genta、Marques, Dalila、Martin, Rebecca、Takei, Hajime、Rodriguez-Agudo, Daniel、Hashiguchi, Taishi、LaSalle, Sandra A.

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Northwestern Univ, Dept Med, Chicago, IL 60611 USA

Univ Calif San Francisco, Sch Med, San Francisco, CA USA

Virginia Commonwealth Univ, Dept Biochem & Mol Biophys, Richmond, VA 23298 USA

Virginia Commonwealth Univ, Dept Internal Med, Med Coll Virginia Campus, Richmond, VA 23284 USA

Juntendo Univ, Fac Med, Dept Pediat, Tokyo, Japan

Hlth Sci Univ Hokkaido, Sch Pharmaceut Sci, Tobetsu, Hokkaido, Japan

Bile Acid Inst, Junshin Clin, Tokyo, Japan

Hunter Holmes McGuire Vet Adm Med Ctr, Dept Vet Affairs, Richmond, VA 23249 USA

Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA

SMC Labs Inc, Tokyo, Japan

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2020

10.1194/jlr.RA120000924

Journal of lipid research.

Journal of lipid research.

ISSN：0022-2275
年,卷(期)：2020.61(12)
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