Padiadpu Jyothi, Spooner Melinda H, Li Zhipeng, Newman Nolan, Löhr Christiane V, Apperson K Denise, Dzutsev Amiran, Trinchieri Giorgio, Shulzhenko Natalia, Morgun Andrey, Jump Donald B
College of Pharmacy, Oregon State University, Corvallis, OR, United States.
Nutrition Program, Colleges of Public Health and Human Sciences, Oregon State University, Corvallis, OR, United States.
Front Nutr. 2023 Aug 7;10:1147602. doi: 10.3389/fnut.2023.1147602. eCollection 2023.
Nonalcoholic fatty liver disease (NAFLD) is a global health problem. Identifying early gene indicators contributing to the onset and progression of NAFLD has the potential to develop novel targets for early therapeutic intervention. We report on the early and late transcriptomic signatures of western diet (WD)-induced nonalcoholic steatohepatitis (NASH) in female and male mice, with time-points at 1 week and 40 weeks on the WD. Control mice were maintained on a low-fat diet (LFD) for 1 and 40 weeks.
The approach included quantitation of anthropometric and hepatic histology markers of disease as well as the hepatic transcriptome.
Only mice fed the WD for 40 weeks revealed evidence of NASH, i.e., hepatic steatosis and fibrosis. RNASeq transcriptome analysis, however, revealed multiple cell-specific changes in gene expression after 1 week that persisted to 40 weeks on the WD. These early markers of disease include induction of acute phase response (), fibrosis () and NASH associated macrophage (NAM, i.e., ). We also noted the induction of transcripts associated with metabolic syndrome, including and . Finally, 1 week of WD feeding was sufficient to significantly induce TNFα, a cytokine involved in both hepatic and systemic inflammation.
This study revealed early onset changes in the hepatic transcriptome that develop well before any anthropometric or histological evidence of NALFD or NASH and pointed to cell-specific targeting for the prevention of disease progression.
非酒精性脂肪性肝病（NAFLD）是一个全球性的健康问题。确定导致NAFLD发病和进展的早期基因指标，有可能开发出早期治疗干预的新靶点。我们报告了西方饮食（WD）诱导的雌性和雄性小鼠非酒精性脂肪性肝炎（NASH）的早期和晚期转录组特征，时间点为WD喂养1周和40周。对照小鼠维持低脂饮食（LFD）1周和40周。
该方法包括对疾病的人体测量和肝脏组织学标志物以及肝脏转录组进行定量分析。
只有喂养WD 40周的小鼠出现了NASH的证据，即肝脂肪变性和纤维化。然而，RNA测序转录组分析显示，1周后基因表达出现了多种细胞特异性变化，并在WD喂养40周时持续存在。这些疾病的早期标志物包括急性期反应（）、纤维化（）和NASH相关巨噬细胞（NAM，即）的诱导。我们还注意到与代谢综合征相关的转录本的诱导，包括和。最后，喂养WD 1周足以显著诱导TNFα，这是一种参与肝脏和全身炎症的细胞因子。
本研究揭示了肝脏转录组的早期变化，这些变化在出现任何NAFLD或NASH的人体测量或组织学证据之前就已发生，并指出了预防疾病进展的细胞特异性靶点。
