Environmental Toxicology Program, Clemson University, Clemson, SC, United States of America.
Biological Sciences, Clemson University, Clemson, SC, United States of America.
PLoS One. 2020 Mar 10;15(3):e0229896. doi: 10.1371/journal.pone.0229896. eCollection 2020.
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.
非酒精性脂肪性肝病 (NAFLD) 是最常见的肝脏疾病；然而，向非酒精性脂肪性肝炎 (NASH) 的进展与大多数不良结局相关。CYP2B 代谢多种外源性和内源性物质，雄性 Cyp2b 基因敲除小鼠在饮食诱导肥胖 (DIO) 状态下，NAFLD 加重。然而，DIO 研究进行的时间不够长，无法评估向 NASH 的进展。因此，为了评估 Cyp2b 在从 NAFLD 向 NASH 进展的脂肪性肝病中的作用，我们用正常饮食 (ND) 或胆碱缺乏、L-氨基酸定义的高脂肪饮食 (CDAHFD) 处理野生型 (WT) 和 Cyp2b 基因敲除小鼠 8 周，并确定代谢和分子变化。CDAHFD 喂养的 WT 雌性小鼠比 Cyp2b 基因敲除小鼠体重增加更多，肝脏和白色脂肪组织质量更大；而雄性无论基因型如何都经历了饮食诱导的体重减轻。两种性别 CDAHFD 喂养的小鼠血清肝损伤生物标志物均升高；然而，与 WT 小鼠相比，CDAHFD 喂养的 Cyp2b 基因敲除雌性小鼠血清 ALT、AST 和 ASP 浓度显著降低，表明 Cyp2b 基因敲除雌性小鼠免受肝损伤。在两种性别中，RNA-seq 数据的层次聚类表明，在 CDAHFD 喂养的 Cyp2b 基因敲除小鼠与 WT 小鼠中，有几个基因本体论的反应不同（脂质代谢 >纤维化 >炎症）。油红 O 染色和直接甘油三酯测量证实，CDAHFD 喂养的 Cyp2b 基因敲除雌性小鼠免受 NAFLD 的影响。CDAHFD 喂养的 Cyp2b 基因敲除小鼠的纤维化在转录组和血清标志物方面表现出相似的变化，表明由于糖皮质激素介导的免疫反应抑制，炎症较少。与雌性相反，CDAHFD 喂养的 Cyp2b 基因敲除雄性小鼠的甘油三酯水平更高。结果表明，雌性 Cyp2b 基因敲除小鼠免受 NAFLD 的影响，而雄性 Cyp2b 基因敲除小鼠更易患 NAFLD，NASH 发展的显著变化较少。这项研究证实，NAFLD 发展的增加不一定导致进展性 NASH。此外，它表明 Cyp2b 在脂肪性肝病中的作用因性别而异。
