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

doi:10.1194/jlr.ra120000924

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.

Highlights

Supplementary key words cholesterol toxicity oxysterol 7 hydroxylase inflammation liver injury nonalcoholic fatty liver disease nonalcoholic steatohepatitis oxysterol nonalcoholic fatty liver
Our laboratory hypothesized that liver lipid excess in NAFLD and NASH might be linked to dysregulation of cholesterol metabolism through the alternative pathway of bile acid synthesis (Fig. 1A) [11]
Based on findings obtained in the steroidogenic acute regulatory protein (StarD1) overexpression model, we examined the role of Cyp7b1 and hepatic oxysterols with NAFLD progression using a diet-induced NASH mouse model

Summary

Introduction

Insulin resistance and lipid excess within the liver are considered as the earliest markers or evidence of progression of NAFLD followed by inflammation and subsequent fibrosis [6]. Excess liver lipid is contributed to by increased de novo fatty acid synthesis within the liver, further exacerbating dietary induced liver lipid excess [7]. What complicates this relatively straightforward sequence of metabolic events is that only a small percentage of those with fatty liver progress to NASH. Our laboratory hypothesized that liver lipid excess in NAFLD and NASH might be linked to dysregulation of cholesterol metabolism through the alternative pathway of bile acid synthesis (Fig. 1A) [11].

Methods

Results

Conclusion