Characterization of metabolomic alterations in two stages of metabolic dysfunction-associated steatotic liver disease (MASLD) in an experimental animal model

IF 0.3 Q4 NUTRITION & DIETETICS

CAHIERS DE NUTRITION ET DE DIETETIQUE Pub Date : 2026-08-01 Epub Date: 2026-09-24 DOI:10.1016/j.cnd.2026.08.037

Gisela Kuhn, Andrés Trostchansky, Verónica Gonzalez, Claudio Bernal, Jimena Lavandera

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引用次数: 0

Abstract

Objective

The present investigation study aimed to characterize metabolomic alterations associated with two stages of metabolic dysfunction-associated steatotic liver disease (MASLD) in a murine model fed a cafeteria (CAF) diet.

Methods

Male Wistar rats (Ethics Committee approval No. CE2021-85), were fed either a control (C) -AIN93M- or a CAF diet for 90 or 150 days (C90, C150, CAF90, and CAF150 groups). Nutriomic parameters related to obesity, hepatic steatosis, and inflammation were evaluated by analyzing (i) obesity indices: body weight -BW-, abdominal circumference -AC-, body mass -BMI-, and Lee indexes; (ii) macro- and micro-steatosis by H&E staining, liver fibrosis (PSR); serum and hepatic triacylglycerol (TAG) and cholesterol (Chol) contents, and glycemia levels; (iii) hepatic gene expression related to lipogenesis, b-oxidation, fatty acids (FA) uptake and transport, and VLDL-TG synthesis determined by RT-qPCR; iv) FA profile by GC-FID and oxylipids levels associated with inflammatory status by HPLC-MS/MS. Data were analyzed by two-way ANOVA (diet × time), followed by Tukey's post hoc test. Statistical significance was set at P < 0.05.

Results

CAF90 showed marked micro- and macro-steatosis accompanied by increased hepatic TAG (20%), Chol (33%), and collagen deposition (79%). These alterations were further exacerbated in CAF150 group (465%, 463%, 124%, 19%, and 142%, respectively). The mechanisms involved in the progression of steatotic liver disease in CAF150 group were associated with reduced β-oxidation (PPARα: −37% and CPT1a: −42%) and impaired VLDL-TG secretion (MTTP: −21%), together with increased FA transport (FATP2: 52% and FATP5: 68%) and esterification (DGAT2: 52%). Furthermore, liver disease progression paralleled increased adiposity, as evidenced by higher BW (17%), AC (10%), Lee Index (11%), and BMI (30%). These changes were accompanied by a pronounced inflammation state reflected by elevated pro-inflammatory oxylipid levels: TxB2 (190%), PGE2 (100%), PGD2 (186%), 5-HETE (423%), 11-HETE (80%), 15-HETE (177%) and 17-HETE (182%), 9-HODE (45%) and 13-HODE (94%). These results are associated with an imbalance between hepatic arachidonic acid and eicosapentanoic acid levels.

Conclusion

The CAF diet induced progressive MASLD, leading to worsening metabolic dysfunction over time. Disease progression was associated with impaired β-oxidation and VLDL-TG secretion, resulting in exacerbated lipid accretion, oxidative stress, and inflammation in this murine model.

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实验动物模型中代谢功能障碍相关脂肪变性肝病（MASLD）两个阶段代谢组学改变的特征

目的本研究旨在描述在自助餐厅（CAF）饮食的小鼠模型中与代谢功能障碍相关的脂肪变性肝病（MASLD）两个阶段相关的代谢组学改变。本研究旨在描述在自助餐厅（CAF）饮食的小鼠模型中与代谢功能障碍相关的脂肪变性肝病（MASLD）两个阶段相关的代谢组学改变。方法小型Wistar大鼠(伦理委员会批准号：CE2021-85)，分别饲喂对照(C) - ain93m -或CAF饲粮90或150 d （C90、C150、CAF90和CAF150组）。通过分析(1)肥胖指标：体重- bw -、腹围- ac -、体重- bmi -和Lee指数来评估与肥胖、肝脂肪变性和炎症相关的营养参数；（ii） H&；E染色的宏观和微观脂肪变性，肝纤维化（PSR）；血清和肝脏甘油三酯（TAG）、胆固醇（Chol）含量及血糖水平；（iii）通过RT-qPCR检测与脂肪生成、b-氧化、脂肪酸（FA）摄取和运输、VLDL-TG合成相关的肝脏基因表达；iv) GC-FID分析FA谱，HPLC-MS/MS分析与炎症状态相关的氧脂水平。数据采用双因素方差分析（饮食×时间），并进行Tukey事后检验。P <； 0.05为统计学意义。雄性Wistar大鼠(伦理委员会批准号：CE2021-85)，分别饲喂对照(C) - ain93m -或CAF饲粮90或150 d （C90、C150、CAF90和CAF150组）。通过分析(1)肥胖指标：体重- bw -、腹围- ac -、体重- bmi -和Lee指数来评估与肥胖、肝脂肪变性和炎症相关的营养参数；（ii） H&；E染色的宏观和微观脂肪变性，肝纤维化（PSR）；血清和肝脏甘油三酯（TAG）、胆固醇（Chol）含量及血糖水平；（iii）通过RT-qPCR检测与脂肪生成、b-氧化、脂肪酸（FA）摄取和运输、VLDL-TG合成相关的肝脏基因表达；iv) GC-FID分析FA谱，HPLC-MS/MS分析与炎症状态相关的氧脂水平。数据采用双因素方差分析（饮食×时间），并进行Tukey事后检验。P <； 0.05为统计学意义。结果scaf90显示明显的微观和宏观脂肪变性，并伴有肝TAG（20%）、Chol（33%）和胶原沉积（79%）的增加。这些变化在CAF150组进一步加剧（分别为465%、463%、124%、19%和142%）。CAF150组脂肪变性肝病进展的机制与β-氧化减少（PPARα: - 37%, CPT1a: - 42%）和VLDL-TG分泌受损（MTTP: - 21%）以及FA转运增加（FATP2: 52%, FATP5: 68%）和酯化（DGAT2: 52%）有关。此外，肝脏疾病进展与肥胖增加并行，如BW（17%）、AC（10%）、Lee指数（11%）和BMI（30%）升高。这些变化伴随着明显的炎症状态，反映在促炎氧脂水平升高：TxB2（190%）、PGE2（100%）、PGD2（186%）、5-HETE（423%）、11-HETE（80%）、15-HETE（177%）和17-HETE（182%）、9-HODE（45%）和13-HODE（94%）。这些结果与肝脏花生四烯酸和二十碳五烯酸水平的不平衡有关。CAF90显示明显的微观和宏观脂肪变性，并伴有肝TAG（20%）、Chol（33%）和胶原沉积（79%）的增加。这些变化在CAF150组进一步加剧（分别为465%、463%、124%、19%和142%）。CAF150组脂肪变性肝病进展的机制与β-氧化减少（PPARα: - 37%, CPT1a: - 42%）和VLDL-TG分泌受损（MTTP: - 21%）以及FA转运增加（FATP2: 52%, FATP5: 68%）和酯化（DGAT2: 52%）有关。此外，肝脏疾病进展与肥胖增加并行，如BW（17%）、AC（10%）、Lee指数（11%）和BMI（30%）升高。这些变化伴随着明显的炎症状态，反映在促炎氧脂水平升高：TxB2（190%）、PGE2（100%）、PGD2（186%）、5-HETE（423%）、11-HETE（80%）、15-HETE（177%）和17-HETE（182%）、9-HODE（45%）和13-HODE（94%）。这些结果与肝脏花生四烯酸和二十碳五烯酸水平的不平衡有关。结论CAF饮食可诱导进行性MASLD，随着时间的推移导致代谢功能障碍恶化。在该小鼠模型中，疾病进展与β-氧化和VLDL-TG分泌受损相关，导致脂质增加、氧化应激和炎症加剧。CAF饮食诱导进行性MASLD，随着时间的推移导致代谢功能障碍恶化。在该小鼠模型中，疾病进展与β-氧化和VLDL-TG分泌受损相关，导致脂质增加、氧化应激和炎症加剧。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CAHIERS DE NUTRITION ET DE DIETETIQUE NUTRITION & DIETETICS-

CiteScore

0.60

自引率

33.30%

发文量

审稿时长

65 days

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