Time course of western diet (WD) induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr-/- mice.
Time course of western diet (WD) induced nonalcoholic steatohepatitis (NASH) in female and male Ldlr-/- mice.
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DOI：
10.1371/journal.pone.0292432
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
非酒精性脂肪肝（NAFLD）是一个全球性的健康问题。识别导致NAFLD发生和发展的因素有可能指导对抗NAFLD的新策略。我们在年龄匹配的雌性和雄性Ldlr-/-小鼠中检测了西方饮食（WD）诱导的NAFLD的时间过程及其向非酒精性脂肪性肝炎（NASH）的进展，时间点分别为WD的1、4、8、20和40周。对照组为Ldlr-/-小鼠，维持1周和40周的纯低脂饮食（LFD）。该方法包括人体测量、血浆和肝脏疾病标志物的定量，以及肝脏组织学、脂质、氧脂质、基因表达和选定的代谢物。饲喂WD一周后，肝脏必需脂肪酸（EFAs: 18:2, ω6, 18:3, ω3）显著降低，而饲喂WD 4周后，许多C20-22 ω3和ω6多不饱和脂肪酸（PUFA）和PUFA衍生的氧脂类含量下降。此外，雌性和雄性小鼠在WD治疗一周后，肝脏炎症标志物（CD40、CD44、Mcp1、Nlrp3、TLR2、TLR4、Trem2）的表达均显著升高。在为期40周的WD喂养研究中，这些指标继续增加。WD对肝脏EFA和炎症的影响先于WD引起的体重、胰岛素抵抗（HOMA-IR）、氧化应激状态（GSH/GSSG比率）以及大脂肪变性、细胞外基质重塑和纤维化的组织学和基因表达标志物的显著变化。我们的研究结果证实，给Ldlr-/-小鼠喂食WD可迅速降低肝脏EFAs，并诱导与NASH相关的关键炎症标志物。由于EFAs在炎症中有明确的作用，肝脏炎症在NASH中起主要作用，我们建议早期临床评估EFA状态并纠正EFA缺陷可能有助于降低NASH的严重程度。
Nonalcoholic fatty liver disease (NAFLD) is a global health problem. Identification of factors contributing to the onset and progression of NAFLD have the potential to direct novel strategies to combat NAFLD. We examined the time course of western diet (WD)-induced NAFLD and its progression to nonalcoholic steatohepatitis (NASH) in age-matched female and male Ldlr-/- mice, with time-points at 1, 4, 8, 20 and 40 weeks on the WD. Controls included Ldlr-/- mice maintained on a purified low-fat diet (LFD) for 1 and 40 weeks. The approach included quantitation of anthropometric, plasma and liver markers of disease, plus hepatic histology, lipids, oxylipins, gene expression and selected metabolites. One week of feeding the WD caused a significant reduction in hepatic essential fatty acids (EFAs: 18:2, ω6, 18:3, ω3) which preceded the decline in many C20-22 ω3 and ω6 polyunsaturated fatty acids (PUFA) and PUFA-derived oxylipins after 4 weeks on the WD. In addition, expression of hepatic inflammation markers (CD40, CD44, Mcp1, Nlrp3, TLR2, TLR4, Trem2) increased significantly in both female & male mice after one week on the WD. These markers continued to increase over the 40-week WD feeding study. WD effects on hepatic EFA and inflammation preceded all significant WD-induced changes in body weight, insulin resistance (HOMA-IR), oxidative stress status (GSH/GSSG ratio) and histological and gene expression markers of macrosteatosis, extracellular matrix remodeling and fibrosis. Our findings establish that feeding Ldlr-/- mice the WD rapidly lowered hepatic EFAs and induced key inflammatory markers linked to NASH. Since EFAs have an established role in inflammation and hepatic inflammation plays a major role in NASH, we suggest that early clinical assessment of EFA status and correcting EFA deficiencies may be useful in reducing NASH severity.
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