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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1629-1644
Number of pages16
JournalJournal of lipid research
Volume61
Issue number12
DOIs
StatePublished - Dec 2020

Keywords

  • Cholesterol toxicity
  • Inflammation
  • Liver injury
  • Nonalcoholic fatty liver
  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Oxysterol
  • Oxysterol 7α- hydroxylase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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