Treatment with 1.25% cholesterol enriched diet produces severe fatty liver disease characterized by advanced fibrosis and inflammation and impaired autophagy in mice

IF 4.8 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Nutritional Biochemistry Pub Date : 2024-08-05 DOI:10.1016/j.jnutbio.2024.109711
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is reaching pandemic proportions due to overnutrition. The understanding of advanced stages that recapitulate the human pathology is of great importance to get a better mechanistic insight. We hypothesized that feeding of WT (C57BL) mice with a diet containing a high content of fat (21%), sugar (41.5%) and 1.25% of cholesterol (called from now on high fat, sucrose and cholesterol diet, HFSCD) will reproduce the characteristics of disease severity. Analysis of 16 weeks HFSCD-fed mice demonstrated increased liver weight and plasmatic liver damage markers compared with control diet (CD)-fed mice. HFSCD-fed mice developed greater hepatic triglyceride, cholesterol and NEFA content, inflammation and NAFLD activity score (NAS) indicating an advanced disease. HFSCD-fed mice displayed augmented hepatic total CD3+ T and Th9 lymphocytes, as well as reduced Th2 lymphocytes and CD206 anti-inflammatory macrophages. Moreover, T cells and anti-inflammatory macrophages correlated positively and inversely, respectively, with intrahepatic cholesterol content. Consistently, circulating cytotoxic CD8+ T lymphocytes, Th1, and B cell levels were elevated in HFSCD-fed WT mice. Hepatic and adipose tissue expression analysis demonstrated changes in fibrotic and metabolic genes related with cholesterol, triglycerides, and fatty acid synthesis in HFSCD-fed WT. These mice also exhibited reduced antioxidant capacity and autophagy and elevated ERK signaling pathway activation and CHOP levels. Our results indicate that the feeding with a cholesterol-enriched diet in WT mice produces an advanced NAFLD stage with fibrosis, characterized by deficient autophagy and ER stress along with inflammasome activation partially via ERK pathway activation.

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用富含 1.25% 胆固醇的饮食治疗小鼠会产生严重的脂肪肝,其特点是肝纤维化、炎症和自噬功能受损。
由于营养过剩,非酒精性脂肪肝(NAFLD)已达到大流行的程度。了解重现人类病理的晚期阶段对更好地了解机理非常重要。我们假设,用脂肪(21%)、糖(41.5%)和胆固醇(1.25%)含量较高的食物(即高脂肪、蔗糖和胆固醇食物,HFSCD)喂养 WT(C57BL)小鼠,将再现疾病严重程度的特征。对喂食高脂蔗糖胆固醇饮食 16 周的小鼠进行的分析表明,与喂食对照饮食(CD)的小鼠相比,肝脏重量和浆液性肝脏损伤指标均有所增加。喂食HFSCD的小鼠肝脏甘油三酯、胆固醇和NEFA含量更高,炎症和非酒精性脂肪肝活动评分(NAS)也更高,表明疾病已进入晚期。喂食HFSCD的小鼠显示肝脏CD3+ T和Th9淋巴细胞总数增加,Th2淋巴细胞和CD206抗炎巨噬细胞减少。此外,T细胞和抗炎巨噬细胞分别与肝内胆固醇含量呈正相关和反相关。同样,在喂食 HFSCD 的 WT 小鼠中,循环中的细胞毒性 CD8+ T 淋巴细胞、Th1 和 B 细胞水平升高。肝脏和脂肪组织的表达分析表明,在喂食 HFSCD 的 WT 小鼠中,与胆固醇、甘油三酯和脂肪酸合成有关的纤维化和代谢基因发生了变化。这些小鼠还表现出抗氧化能力和自噬能力降低,ERK 信号通路激活和 CHOP 水平升高。我们的研究结果表明,以富含胆固醇的饮食喂养 WT 小鼠会导致非酒精性脂肪肝晚期并伴有纤维化,其特点是自噬和 ER 应激不足,以及部分通过 ERK 通路激活炎性体。
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来源期刊
Journal of Nutritional Biochemistry
Journal of Nutritional Biochemistry 医学-生化与分子生物学
CiteScore
9.50
自引率
3.60%
发文量
237
审稿时长
68 days
期刊介绍: Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.
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