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 language | English (US) |
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Pages (from-to) | 1629-1644 |
Number of pages | 16 |
Journal | Journal of lipid research |
Volume | 61 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2020 |
Funding
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.
Keywords
- Cholesterol toxicity
- Inflammation
- Liver injury
- Nonalcoholic fatty liver
- Nonalcoholic fatty liver disease
- Nonalcoholic steatohepatitis
- Oxysterol
- Oxysterol 7α- hydroxylase
ASJC Scopus subject areas
- Endocrinology
- Biochemistry
- Cell Biology