Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease; however, progression to nonalcoholic steatohepatitis (NASH) is associated with most adverse outcomes. CYP2B metabolizes multiple xeno- and endobiotics, and male Cyp2b-null mice are diet-induced obese (DIO) with increased NAFLD. However, the DIO study was not performed long enough to assess progression to NASH. Therefore, to assess the role of Cyp2b in fatty liver disease progression from NAFLD to NASH, we treated wildtype (WT) and Cyp2b-null mice with a normal diet (ND) or choline-deficient, L-amino acid-defined high fat diet (CDAHFD) for 8 weeks and determined metabolic and molecular changes. CDAHFD-fed WT female mice gained more weight and had greater liver and white adipose tissue mass than their Cyp2b-null counterparts; males experienced diet-induced weight loss regardless of genotype. Serum biomarkers of liver injury increased in both CDAHFD-fed female and male mice; however CDAHFD-fed Cyp2b-null females exhibited significantly lower serum ALT, AST, and ASP concentrations compared to WT mice, indicating Cyp2b-null females were protected from liver injury. In both genders, hierarchical clustering of RNA-seq data demonstrates several gene ontologies responded differently in CDAHFD-fed Cyp2b-null mice compared to WT mice (lipid metabolism > fibrosis > inflammation). Oil Red O staining and direct triglycerides measurements confirmed that CDAHFD-fed Cyp2b-null females were protected from NAFLD. CDAHFD-fed Cyp2b-null mice showed equivocal changes in fibrosis with transcriptomic and serum markers suggesting less inflammation due to glucocorticoid-mediated repression of immune responses. In contrast to females, CDAHFD-fed Cyp2b-null males had higher triglyceride levels. Results indicate that female Cyp2b-null mice are protected from NAFLD while male Cyp2b-null mice are more susceptible to NAFLD, with few significant changes in NASH development. This study confirms that increased NAFLD development does not necessarily lead to progressive NASH. Furthermore, it indicates a role for Cyp2b in fatty liver disease that differs based on gender.
Highlights
Liver disease often progresses from nonalcoholic fatty liver disease (NAFLD) to more severe diseases such as nonalcoholic steatohepatitis (NASH), fibrosis including cirrhosis, and liver cancer [1]
CDAHFD-fed male mice weighed significantly less than their normal diet counterparts, indicating that diet was the primary modifier of weight in males, not genotype (Fig 1B)
Cyp2b-null-mediated gender differences in fatty liver diseases few differences in fibrosis markers between CDAHFD-fed WT and Cyp2b-null females, hydroxyproline levels were slighty lower in Cyp2b-null female mice
Summary
Liver disease often progresses from nonalcoholic fatty liver disease (NAFLD) to more severe diseases such as nonalcoholic steatohepatitis (NASH), fibrosis including cirrhosis, and liver cancer [1]. NAFLD is defined as the presence of 5% hepatic steatosis in the absence of other liver diseases [2], yet less than 25% of patients with NAFLD develop NASH [5]. In some cases the hepatic intracellular accumulation of lipids in fatty liver disease can develop into NASH as inflammation, injury and fibrosis progress due to anti-lipotoxic protection failure [5]. Studies have shown that steatosis may not affect NASH development [7]; the pathogenesis of NASH remains controversial. Fibrosis progression occurs in most patients with NASH and cirrhosis is the main histological feature associated with mortality of NASH patients [8]
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