Journal
JOURNAL OF LIPID RESEARCH
Volume 61, Issue 12, Pages 1629-1644Publisher
ELSEVIER
DOI: 10.1194/jlr.RA120000924
Keywords
cholesterol toxicity; oxysterol 7 alpha-hydroxylase; inflammation; liver injury; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; oxysterol; nonalcoholic fatty liver
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Funding
- Gilead Sciences Liver Research Award 2016
- Veterans Administration Veterans Affairs Merit Award [I01 BX000197-07]
- NIH
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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.
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