Apolipoprotein A-Ⅰ Prevents High-fat Diet-induced Intestinal Mucosal Barrier Damage In Ulcerative Colitis By Regulating PI3K/AKT Pathway

BackgroundUlcerative colitis is a chronic non-specific inflammatory disease of the intestine.To date,there is no cure for ulcerative colitis due to insufficient understanding of the pathogenesis and etiology of the disease.A high-fat diet is an important contributing factor to ulcerative colitis,and the incidence of ulcerative colitis in the population has been increasing year by year in recent years as the fat content of the dietary structure has been gradually rising.Dietary fat can damage the structure and function of the intestinal barrier by affecting intestinal flora,tight junctions,and oxidative stress.Therefore,an in-depth study of the etiology and pathogenesis of ulcerative colitis and further understanding of the relationship between high-fat diet and ulcerative colitis are of great significance for the development of new treatments for ulcerative colitis.Apolipoprotein APOA-Ⅰ is the main protein component of HDL and plays an important role in anti-inflammation and immunosuppression.Available studies have shown that a highfat diet can inhibit APOA-I production in mice.Scavenger receptor class B type Ⅰ is the main effector receptor of APOA-Ⅰ,which mainly activates PI3K/AKT signaling pathway.PI3K/AKT signaling pathway is mainly related to cell metabolism,differentiation,proliferation and apoptosis,and is involved in angiogenesis,proliferation and migration of tumors.Current animal studies at home and abroad have shown that the PI3K/AKT pathway can maintain the epithelial structural integrity of a variety of tissues.Therefore,we speculate that APOA-I may regulate the expression of intestinal tight junctions and thus affect the intestinal barrier through the PI3K/AKT pathway.ObjectivesTo investigate the correlation between APOA-Ⅰ and ulcerative colitis;to clarify the effect of APOA-I on colonic mucosal tight junction proteins;and to verify the barrier protective effect of PI3K/AKT pathway on intestinal epithelium.MethodsPart Ⅰ:Data collection from UC patients and healthy population:serum APOA-Ⅰ,hemoglobin,hematocrit data and colonoscopy reports were collected from UC patients and healthy population in the past five years to assess the relationship between APOA-Ⅰ levels and UC;colonic mucosa was collected from UC patients and healthy population to assess the expression level of APOA-I by RT-PCR.Part Ⅱ:APOA-Ⅰ holo-deficient mice were introduced,tight junction proteins and PI3K/AKT pathway molecules were measured and analyzed to determine the preliminary relationship between APOA-I and colonic mucosal tight junction proteins;a mouse colitis model was established,and the effect of SR-BI/PI3K/AKT pathway on tight junction proteins in mice was analyzed through the intervention of APOA-I mimetic peptide 4F and SR-BI inhibitor BLT-1.Conclusion1.The expression level of APOA-Ⅰ decreased in patients with ulcerative colitis,and the level of APOA-Ⅰ decreased more significantly as the disease severity of UC increased,suggesting that APOA-I may reflect the disease severity of UC.Age and gender also affect the expression of APOA-Ⅰ in ulcerative colitis,which may explain the different phenotypes of UC in patients of different ages and genders.2.APOA-Ⅰ deficiency leads to colonic mucosal barrier damage,mainly manifested by down-regulation of tight junction protein expression;APOA-I mimetic peptide 4F can regulate intestinal tight junction protein expression through PI3K/AKT pathway,which in turn maintains the integrity of the intestinal barrier.