Department of Clinical and Molecular Medicine, "La Sapienza" University, Rome, Italy.
J Hepatol. 2011 May;54(5):975-83. doi: 10.1016/j.jhep.2010.09.020. Epub 2010 Oct 29.
BACKGROUND & AIMS: Excess fatty acid oxidation and generation of reactive carbonyls with formation of advanced lipoxidation endproducts (ALEs) is involved in nonalcoholic steatohepatitis (NASH) by triggering inflammation, hepatocyte injury, and fibrosis. This study aimed at verifying the hypothesis that ablation of the ALE-receptor galectin-3 prevents experimental NASH by reducing receptor-mediated ALE clearance and downstream events.
Galectin-3-deficient (Lgals3(-/-)) and wild type (Lgals3(+/+)) mice received an atherogenic diet or standard chow for 8 months. Liver tissue was analyzed for morphology, inflammation, cell and matrix turnover, lipid metabolism, ALEs, and ALE-receptors.
Steatosis was significantly less pronounced in Lgals3(-/-) than Lgals3(+/+) animals on atherogenic diet. NASH, invariably detected in Lgals3(+/+) mice, was observed, to a lower extent, only in 3/8 Lgals3(-/-) mice, showing less inflammatory, degenerative, and fibrotic phenomena than Lgals3(+/+) mice. This was associated with higher circulating ALE levels and lower tissue ALE accumulation and expression of other ALE-receptors. Up-regulation of hepatic fatty acid synthesis and oxidation, inflammatory cell infiltration, pro-inflammatory cytokines, endoplasmic reticulum stress, hepatocyte apoptosis, myofibroblast transdifferentiation, and impaired Akt phosphorylation were also significantly attenuated in Lgals3(-/-) animals. Galectin-3 silencing in liver endothelial cells resulted in reduced N(ε)-carboxymethyllysine-modified albumin uptake and ALE-receptor expression.
Galectin-3 ablation protects from diet-induced NASH by decreasing hepatic ALE accumulation, with attenuation of inflammation, hepatocyte injury, and fibrosis. It also reduced up-regulation of lipid synthesis and oxidation causing less fat deposition, oxidative stress, and possibly insulin resistance. These data suggest that galectin-3 is a major receptor involved in ALE uptake by the liver.
过量脂肪酸氧化和活性羰基的生成，导致晚期糖基化终末产物（ALEs）的形成，在非酒精性脂肪性肝炎（NASH）中通过触发炎症、肝细胞损伤和纤维化起作用。本研究旨在验证以下假设，即通过减少受体介导的 ALE 清除和下游事件，ALEs 受体半乳糖凝集素-3 的消融可预防实验性 NASH。
缺乏半乳糖凝集素-3（Lgals3(-/-)）和野生型（Lgals3(+/+)）小鼠分别接受致动脉粥样硬化饮食或标准饲料 8 个月。分析肝组织形态、炎症、细胞和基质更新、脂质代谢、ALEs 和 ALE 受体。
在致动脉粥样硬化饮食中，Lgals3(-/-)小鼠的脂肪变性明显轻于 Lgals3(+/+)动物。NASH 在所有 Lgals3(+/+)小鼠中均被检测到，但在 8 只 Lgals3(-/-)小鼠中，仅在 3 只中观察到程度较轻，其炎症、变性和纤维化现象较 Lgals3(+/+)小鼠少。这与循环 ALE 水平升高和组织 ALE 积聚及其他 ALE 受体表达降低有关。肝脂肪酸合成和氧化的上调、炎症细胞浸润、促炎细胞因子、内质网应激、肝细胞凋亡、肌成纤维细胞转分化以及 Akt 磷酸化受损在 Lgals3(-/-)动物中也明显减弱。肝内皮细胞中半乳糖凝集素-3 的沉默导致 N(ε)-羧甲基赖氨酸修饰的白蛋白摄取和 ALE 受体表达减少。
半乳糖凝集素-3 的消融通过减少肝脏 ALE 的积聚，减轻炎症、肝细胞损伤和纤维化，从而防止饮食诱导的 NASH。它还减少了脂质合成和氧化的上调，导致脂肪沉积、氧化应激减少，可能还有胰岛素抵抗减少。这些数据表明，半乳糖凝集素-3 是肝脏摄取 ALE 的主要受体之一。
