Angiopoietin-like 4 (ANGPTL4) links creeping fat lipolysis to intestinal muscularis propria hyperplasia: a novel contributor to intestinal stricture formation in Crohn’s disease

Scar build-up in the gut, called intestinal fibrosis, is a hallmark of longstanding Crohn’s disease (CD) and contributes to bowel obstruction and the need for surgical resection. The lack of anti-scarring therapies makes understanding its mechanisms a priority. Recently, a thickening of the muscle layer surrounding the intestine was identified as a major contributor to luminal narrowing and hence patient symptoms in obstructing CD. Mesenteric fat wrapping around the inflamed gut, also known as “creeping fat” (CF) is associated with intestinal muscle thickening in CD. We previously established a functional interaction between CF and proliferation of human intestinal muscle cells (HIMCs) as well as muscle layer thickening. We now found that long-chain free fatty acids released by CF up-regulated a molecule called angiopoietin-like 4 (ANGPTL4) in HIMCs, and ANGPTL4 induced intestinal smooth muscle cell accumulation. More interestingly, ANGPTL4 activated lipolysis in human mesenteric adipocytes to induce free fatty acids secretion. Based on these findings, this proposal will explore the hypothesis that ANGPTL4 centrally mediates the observed interaction between CF and the intestinal muscle layer, driving smooth muscle thickening and intestinal obstruction in CD. ANGPTL4 may be a key and targetable mediator of muscle thickening in CD-associated obstruction.