Background

In Crohn’s disease (CD) wrapping of mesenteric fat around the bowel wall, so called ‘creeping fat’, is highly associated with strictures. The strongest contributor to luminal narrowing in strictures is a thickening of the human intestinal muscularis propria (MP). We hence investigated creeping fat derived factors and their effect on mechanisms of human intestinal MP smooth muscle cell (HIMC) hyperplasia.

Methods

Free fatty acids (FFA) in creeping fat or non-creeping mesenteric fat organ cultures were measured via lipidomic mass spectrometry. Primary HIMC were exposed to FFA and cell proliferation was assessed. Intracellular FFA metabolism pathways and reactive oxygen species were functionally evaluated. Muscle thickness was investigated in dextran sodium sulfate (DSS) colitis with small molecule inhibition of FFA transport and a novel fat deletion mouse model.

Results

Subserosal creeping fat is associated with a markedly thickened MP. Experimental deletion of mesenteric fat (FAT-ATTAC mouse) reduced MP thickness. Human creeping fat conditioned medium strongly upregulated HIMC proliferation. Creeping fat released higher amounts of five long-chain FFA, including palmitate. Inhibition of HIMC long-chain FFA metabolism or FFA uptake into mitochondria through carnitine palmitoyltransferase (CPT)-1 reduced the palmitate induced HIMC proliferation. Blockade of conversion of palmitate into phospholipids reduced HIMC proliferation. Prophylactic inhibition of CPT-1 in experimental DSS colitis did not ameliorate inflammation, but reduced MP thickness.

Conclusion

Creeping fat released long-chain FFA induce a selective proliferative response by HIMC. These results point to creeping fat as a novel contributor to stricture formation in CD.

中文翻译：

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匍匐脂肪衍生的游离脂肪酸诱导肠道固有肌细胞增生——克罗恩病中脂肪与肠道狭窄形成之间的新联系

 背景

在克罗恩病 （CD） 中，肠系膜脂肪包裹肠壁，即所谓的“蠕行脂肪”，与狭窄高度相关。狭窄中管腔狭窄的最主要因素是人肠道固有肌层 （MP） 增厚。因此，我们研究了匍匐脂肪衍生因子及其对人肠道 MP 平滑肌细胞 （HIMC） 增生机制的影响。

 方法

通过脂质组质谱法测量匍匐脂肪或非匍匐肠系膜脂肪器官培养物中的游离脂肪酸 （FFA）。原代 HIMC 暴露于 FFA 并评估细胞增殖。对细胞内 FFA 代谢途径和活性氧进行功能评估。研究葡聚糖硫酸钠 （DSS） 结肠炎的肌肉厚度，小分子抑制 FFA 转运和新型脂肪缺失小鼠模型。

 结果

浆膜下匍匐脂肪与 MP 明显增厚有关。肠系膜脂肪的实验性缺失 （FAT-ATTAC 小鼠） 降低了 MP 厚度。人匍匐脂肪条件培养基强烈上调 HIMC 增殖。蠕动脂肪释放出更多的五长链 FFA，包括棕榈酸酯。通过肉碱棕榈酰转移酶 （CPT）-1 抑制 HIMC 长链 FFA 代谢或 FFA 摄取到线粒体中，减少了棕榈酸酯诱导的 HIMC 增殖。阻断棕榈酸酯转化为磷脂减少了 HIMC 增殖。在实验性 DSS 结肠炎中预防性抑制 CPT-1 并没有改善炎症，但降低了 MP 厚度。

 结论

释放的长链 FFA 蠕动脂肪诱导 HIMC 的选择性增殖反应。这些结果表明，匍匐脂肪是 CD 中狭窄形成的新因素。