肠道癌症，包括食道腺癌、结直肠癌和贲门癌，是肥胖的常见合并症。长时间且过多地向肠道上皮细胞提供大分子营养物质会增加罹患这些癌症的风险，导致肠道干细胞增殖和分化速率的不平衡，从而产生息肉和其他异常生长。我们研究了油脂酰胺等作为营养过剩信号的鞘脂类化合物是否改变干细胞行为，以影响癌症风险。我们对人类腺瘤和肿瘤中的鞘脂类和鞘脂类合成酶进行了分析。此后，我们操纵小鼠的肠道祖细胞、培养的器官样体和果蝇中鞘脂类产生酶的表达，以确定是否鞘脂类改变了干细胞增殖和代谢。抑制脂氨酰丝氨酸转移酶等将饮食脂肪酸和氨基酸转变为产生油脂酰胺和其他鞘脂类的生物合成途径的酶是肠道干细胞稳态的重要调节因子。人类肠道腺瘤中上调了脂氨酰丝氨酸转移酶和其他鞘脂类生物合成途径中的酶。它们产生的油脂酰胺作为促干性信号刺激了过氧化物酶体增殖物激活受体α并诱导脂肪酸结合蛋白-1的表达。这些作用导致肠道祖细胞脂质利用增加和增强增殖能力。油脂酰胺是膳食大分子营养物质、上皮再生和癌症风险之间的关键环节。 Copyright © 2023 AGA Institute. 由 Elsevier Inc. 发布。版权所有。

Cancers of the alimentary tract including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs. differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signals of nutritional excess, alter stem cell behaviors to influence cancer risk.We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism.SPT, which diverts dietary fatty- and amino-acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are upregulated in human intestinal adenomas. They produce ceramides which serve as pro-stemness signals that stimulate peroxisome-proliferator activated receptor alpha and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors.Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.