Abstract
Ulcerative colitis (UC) causes chronic inflammation and damage to the colonic mucosal layer. Recent studies have reported significant changes in phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in UC patients and oral administration of PC has considerable therapeutic effects against UC, suggesting the metabolism of phosphatidylcholine may be involved in the UC development. Our previous work has demonstrated that berberine effectively suppresses inflammation and protects colonic mucosa injury in DSS-induced colitic mice. However, whether the therapeutic effects of berberine are attributed to its action on the PC metabolism remains unknown. In the present study, we have shown that berberine significantly reduces the lysophosphatidylcholine (LPC) levels in the sera of DSS-induced experimental colitis mice and LPS-stimulated macrophage RAW 264.7 cells. The cytosolic phospholipase A2a (PLA2G4A), an enzyme for hydrolyzing PC to LPC, was found to be up-regulated in the colon tissue of experimental colitis mice and inflamed macrophage RAW 264.7 cells. We then demonstrated berberine inhibits the phosphorylation of cytosolic phospholipase A2a (PLA2G4A) in the colon tissue of experimental colitis mice and inflamed macrophage RAW 264.7 cells. Subsequently, we revealed berberine suppressed the expression of pro-inflammatory factors including TNF-alpha and IL-6 through regulating PLA2G4A dysfunction in macrophage RAW 264.7 cells. Mechanistically, we found that berberine directly binds to PLA2G4A and inhibits MAPK/JNK signaling pathway to inhibit PLA2G4A activity in inflammatory status. Therefore, we concluded that berberine inhibits colonic PLA2G4A activity to ameliorate colonic inflammation in experimental colitic mice, suggesting modulation of the PC metabolism via PLA2G4A might be beneficial for establishing new therapies strategy for UC.
Highlights
Ulcerative colitis (UC) and Crohn’s disease (CD) are classified as severe and chronic inflammatory bowel disease (IBD) that causes inflammation and sores in the gastrointestinal tract, in the large intestine (Kaplan, 2015)
We first investigated the effect of berberine on lipid metabolism in experimental colitic mice
We have shown a novel phospholipid-related mechanism underlying the anti-inflammatory effects of berberine
Summary
Ulcerative colitis (UC) and Crohn’s disease (CD) are classified as severe and chronic inflammatory bowel disease (IBD) that causes inflammation and sores (ulcers) in the gastrointestinal tract, in the large intestine (Kaplan, 2015). Lipid metabolism is in relation to chronic inflammation as one of the possible mechanisms involved in the pathogenesis of many inflammatory diseases (Parhofer, 2015). IBD patients have been found with dyslipidemia by several studies, suggesting lipid metabolism and signaling may play key roles in modulating inflammation in IBD (Biyyani et al, 2010; Karaahmet et al, 2013). Lipidomics investigation on IBD patients has revealed alterations of lysophosphatidylcholine (LPC) (Chen et al, 2008; Chander et al, 2014; Fan et al, 2015). The PC and LPC alterations in lipid metabolism and signaling may be involved in the colonic inflammatory responses in IBD, and therapeutic approaches regulating the PC and LPC metabolism or its related enzymes are potentially beneficial for suppressing inflammation in colitis
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