脂解刺激脂蛋白受体 (LSR) 是一种脂质受体，与癌症进展相关。然而，对细胞内代谢的详细影响尚不清楚。我们的目的是阐明胃癌中LSR介导的脂质代谢机制。我们研究了胃癌细胞中脂蛋白给药诱导的脂质代谢变化，并评估了胃癌患者中LSR表达和脂滴形成的意义。还在体外和体内检测了抑制胃癌细胞β-氧化的功效。在胃癌细胞中，LSR促进细胞对脂蛋白的摄取和细胞增殖。此外，在表达高水平LSR的胃癌细胞中抑制LSR可以抵消这两种效应。对人胃癌组织的免疫组织化学分析表明，LSR 导致的脂滴增加是影响预后的因素。 LSR 高表达胃癌细胞的脂质组学分析显示 β-氧化增加。基于这些结果，我们使用了β-氧化抑制剂依托莫克西，发现它可以抑制细胞增殖并抑制LSR。同样，在LSR高表达胃癌细胞的小鼠异种移植模型中，高脂饮食喂养的肿瘤生长效应被依托莫克西抵消，与Ki-67标记指数一致。我们证明脂质被摄取到胃癌中通过LSR作用于细胞，导致β-氧化增加，从而促进癌症进展。控制 LSR 介导的脂质代谢可能是一种新颖的胃癌治疗策略。© 2024。作者获得国际胃癌协会和日本胃癌协会的独家许可。

Lipolysis-stimulated lipoprotein receptor (LSR), a lipid receptor, is associated with cancer progression. However, detailed effects on intracellular metabolism are unclear. We aimed to elucidate the mechanism of LSR-mediated lipid metabolism in gastric cancer.We investigated lipid metabolic changes induced by lipoprotein administration in gastric cancer cells and evaluated the significance of LSR expression and lipid droplets formation in gastric cancer patients. The efficacy of inhibiting β-oxidation in gastric cancer cells was also examined in vitro and vivo.In gastric cancer cells, LSR promoted cellular uptake of lipoprotein and cell proliferation. Furthermore, the inhibition of LSR in gastric cancer cells expressing high levels of LSR counteracted both effects. Immunohistochemical analysis of human gastric cancer tissues showed that the increase in lipid droplets via LSR is a factor that influences prognosis. Lipidomics analysis of LSR-high-expressing gastric cancer cells revealed an increase in β-oxidation. Based on these results, we used etomoxir, a β-oxidation inhibitor, and found that it inhibited cell proliferation as well as the suppression of LSR. Similarly, in a mouse xenograft model of LSR-highly expressing gastric cancer cells, the tumor growth effect of high-fat diet feeding was counteracted by etomoxir, consistent with the Ki-67 labeling index.We demonstrated that lipids are taken up into gastric cancer cells via LSR and cause an increase in β-oxidation, resulting in the promotion of cancer progression. Controlling LSR-mediated lipid metabolism may be a novel therapeutic strategy for gastric cancer.© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.