Grape pomace extract attenuates high fat diet-induced endotoxemia and liver steatosis in mice†

IF 5.1 1区 农林科学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Food & Function Pub Date : 2025-02-19 DOI:10.1039/D4FO06332E
V. Muscia Saez, D. J. Perdicaro, E. Cremonini, V. V. Costantino, A. R. Fontana, P. I. Oteiza and M. A. Vazquez Prieto
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Abstract

Obesity is a prominent global health concern associated with chronic inflammation and metabolic disorders, such as insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). Excessive consumption of saturated fats exacerbates these conditions by increasing intestinal barrier permeability and circulating endotoxins. This study aims to investigate, in a murine model of high-fat diet (HFD)-induced obesity, the potential beneficial effects of a grape pomace extract (GPE), rich in phenolic compounds, at mitigating endotoxemia, and liver steatosis. Underlying mechanisms were characterized in an in vitro model of intestinal inflammation and permeabilization, as induced by tumor necrosis factor alpha (TNFα) in Caco-2 cell monolayers. Consumption of a HFD (60% calories from fat) for 13 weeks induced obesity, insulin resistance, and liver damage, evidenced by higher levels of plasma alanine aminotransferase (ALT), hepatic triglycerides content, and steatosis. In addition, HFD caused metabolic endotoxemia, hepatic toll-like receptor 4 (TLR4) upregulation and inflammation. GPE supplementation significantly reduced body weight and subcutaneous and visceral adipose tissue weight, and attenuated metabolic dysregulation. Furthermore, GPE decreased circulating LPS levels and mitigated HFD-mediated hepatic TLR4 upregulation, nuclear factor kappa B (NF-κB) activation, and downstream expression of proteins involved in oxidative stress and inflammation (NOX4, TNFα, and F4/80). In Caco-2 cells, GPE mitigated TNFα-induced monolayer permeabilization, decreased tight junction (TJ) protein levels, enhanced cellular oxidant production, activated redox-sensitive signaling, i.e., NF-κB and ERK1/2, and increased NOX1 and MLCK mRNA levels, the latter being a key regulator of monolayer permeability. The above findings suggest that GPE may protect against HFD-induced obesity and associated metabolic dysfunction (insulin resistance and NAFLD) by modulating intestinal barrier integrity and related endotoxemia.

Abstract Image

肥胖是一个突出的全球健康问题,与慢性炎症和代谢紊乱(如胰岛素抵抗、2 型糖尿病和非酒精性脂肪肝)有关。过量摄入饱和脂肪会增加肠道屏障的通透性和循环内毒素,从而加剧这些疾病。本研究的目的是在高脂饮食(HFD)诱发肥胖的小鼠模型中,研究富含酚类化合物的葡萄渣提取物(GPE)对减轻内毒素血症和肝脏脂肪变性的潜在有益作用。在肿瘤坏死因子α(TNFα)诱导下,Caco-2 细胞单层体外模型中的肠道炎症和通透性被鉴定为潜在的机制。连续13周摄入高脂饮食(60%的热量来自脂肪)会诱发肥胖、胰岛素抵抗和肝损伤,表现为血浆丙氨酸氨基转移酶(ALT)、肝甘油三酯含量和脂肪变性水平升高。此外,高密度脂蛋白膳食还会引起代谢性内毒素血症、肝脏TLR4受体上调和炎症。补充 GPE 可明显降低体重、皮下和内脏脂肪组织重量,并减轻代谢失调。此外,GPE 还能降低循环中的 LPS 水平,减轻 HFD 介导的肝脏 TLR4 上调、核因子卡巴 B(NF-κB)激活以及氧化应激和炎症相关蛋白(NOX4、TNFα 和 F4/80)的下游表达。在 Caco-2 细胞中,GPE 可减轻 TNFα 诱导的单层渗透,降低紧密连接 (TJ) 蛋白水平,增强细胞氧化剂生成,激活氧化还原敏感信号,即 NF-κB 和 ERK1/2,并提高 NOX1 和 MLCK mRNA 水平,后者是单层渗透性的关键调节因子。上述研究结果表明,GPE 可通过调节肠屏障的完整性和相关的内毒素血症,防止高氟酸脂蛋白诱导的肥胖和相关的代谢功能障碍(胰岛素抵抗和非酒精性脂肪肝)。
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来源期刊
Food & Function
Food & Function BIOCHEMISTRY & MOLECULAR BIOLOGY-FOOD SCIENCE & TECHNOLOGY
CiteScore
10.10
自引率
6.60%
发文量
957
审稿时长
1.8 months
期刊介绍: Food & Function provides a unique venue for physicists, chemists, biochemists, nutritionists and other food scientists to publish work at the interface of the chemistry, physics and biology of food. The journal focuses on food and the functions of food in relation to health.
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