title: Activation of AMPK by chitosan oligosaccharide in intestinal epithelial cells: Mechanism of action and potential applications in intestinal disorders.
abstract: Chitosan oligosaccharide (COS), a biomaterial derived from chitin, is absorbed by intestinal epithelia without degradation and has diverse biological activities including intestinal epithelial function. However, the mode of action is still unclear. This study aimed to investigate the effect of COS on AMP-activated protein kinase (AMPK) in intestinal epithelial cells (IEC) and its potential applications in the intestinal diseases benefited from AMPK activation. COS with molecular weights (MW) from 5,000Da to 14,000Da induced AMPK activation in T84 cells. That with MW of 5,000-Da was the most potent polymer and was used in the subsequent experiments. COS also activated AMPK in other IEC including HT-29 and Caco-2 cells. Mechanism of COS-induced AMPK activation in T84 cells involves calcium-sensing receptor (CaSR)-phospholipase C (PLC)-IP3 receptor channel-mediated calcium release from endoplasmic reticulum (ER). In addition, COS promoted tight junction assembly in T84 cells in an AMPK-dependent manner. COS also inhibited NF-κB transcriptional activity and NF-κB-mediated inflammatory response and barrier disruption via AMPK-independent mechanisms. Interestingly, luminal exposure to COS suppressed cholera toxin-induced intestinal fluid secretion by ∼30% concurrent with AMPK activation in a mouse closed loop model. Importantly, oral administration of COS prevented the development of aberrant crypt foci in a mouse model of colitis-associated colorectal cancer (CRC) via a mechanism involving AMPK activation-induced β-catenin suppression and caspase-3 activation. Collectively, this study reveals a novel action of COS in activating AMPK via CaSR-PLC-IP3 receptor channel-mediated calcium release from ER. COS may be beneficial in the treatment of secretory diarrheas and CRC chemoprevention.
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand. Electronic address: chatchai.mua@mahidol.ac.th.
authors.forename: Chatchai
authors.initials: C
authors.lastname: Muanprasat
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Preedajit
authors.initials: P
authors.lastname: Wongkrasant
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Saravut
authors.initials: S
authors.lastname: Satitsri
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Aekkacha
authors.initials: A
authors.lastname: Moonwiriyakit
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Pawin
authors.initials: P
authors.lastname: Pongkorpsakol
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Tharinee
authors.initials: T
authors.lastname: Mattaveewong
authors.affiliation: Department of Biochemistry, Faculty of Science, Chulalongkorn University, Phayathai, Bangkok 10330, Thailand.
authors.forename: Rath
authors.initials: R
authors.lastname: Pichyangkura
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Rajathevi, Bangkok 10400, Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001397:Azoxymethane; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D048271:Chitosan / Q000494:pharmacology*; D002772:Cholera Toxin / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C577923:CASR protein, mouse; C495267:CTNNB1 protein, mouse; D005765:Gastrointestinal Agents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016328:NF-kappa B; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D051176:beta Catenin; D002772:Cholera Toxin; D048271:Chitosan; D016264:Dextran Sulfate; D055372:AMP-Activated Protein Kinases; D010738:Type C Phospholipases; D053148:Caspase 3; D001397:Azoxymethane; D002118:Calcium
keywords: AMP-activated protein kinase; Chitosan oligosaccharide; Colorectal cancer; Diarrhea; Intestinal epithelial cells