Dietary long-chain fatty acids promote colitis by regulating palmitoylation of STAT3 through CD36-mediated endocytosis
The Western diet, known for its high levels of long-chain fatty acids (LCFAs), is widely acknowledged as a significant trigger for inflammatory bowel disease (IBD). While the association between a high-fat diet and colitis is recognized, the specific effects and mechanisms remain incompletely understood. Our study provides evidence that an LCFA-rich diet disrupts intestinal barrier integrity and exacerbates experimental colitis in mice. Mechanistically, LCFAs upregulate the signal transducer and activator of transcription-3 (STAT3) pathway in the inflammatory model, and genetic knockout of STAT3 effectively mitigates the pro-inflammatory effects of LCFAs on colitis. Specifically, palmitic acid (PA), a representative LCFA, enters intestinal epithelial cells through the cluster of differentiation 36 (CD36) pathway and participates in the palmitoylation cycle of STAT3. Inhibiting this cycle using pharmacological inhibitors such as 2-Bromopalmitate (2-BP) and ML349, as well as DHHC7 knockdown, attenuates PA-induced inflammation. These findings underscore the pivotal role of dietary LCFAs, particularly PA, in the pathogenesis of IBD. Dietary adjustments and targeted modulation present potential therapeutic strategies for managing this condition.