ABCA1 deficiency‐induced cholesterol accumulation aggravates colonic epithelial injury in knockout hamsters

BACKGROUND: ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux, yet its role in inflammatory bowel disease (IBD) remains incompletely understood. This study investigated the consequences of intestinal epithelial cholesterol accumulation-primarily driven by ABCA1 deficiency-on colonic inflammation and the underlying molecular mechanisms. METHODS: ABCA1 knockout (KO) and wild-type (WT) Syrian golden hamsters were fed a high-cholesterol high-fat diet for 12 weeks. Colon specimens were analyzed for pathological changes, inflammatory markers, cholesterol accumulation, and gene expression profiles. Furthermore, in vitro experiments were performed using the human colon epithelial cell line Caco-2. RESULTS: ABCA1 deficiency, in the context of a high-cholesterol high-fat diet, triggered significant colonic inflammation in KO hamsters, characterized by epithelial damage, inflammatory cell infiltration, and elevated pro-inflammatory cytokine levels. These pathological changes were associated with impaired mucosal barrier integrity, a four-fold increase in epithelial cholesterol accumulation, and reduced E-cadherin, ZO-1 and occludin expression. Furthermore, ABCA1 deficiency promoted oxidative stress and induced marked remodeling of the gut microbiota. CONCLUSIONS: Our findings establish a pathogenic role for ABCA1 deficiency in driving colonic epithelial injury and inflammation, suggesting that ABCA1 may play an important role in the pathogenesis of IBD.