Experimental colitis: decreased Octn2 and Atb0+ expression in rat colonocytes induces carnitine depletion that is reversible by carnitine-loaded liposomes.
Carnitine transporters have recently been implicated in susceptibility to inflammatory bowel disease (IBD). Because carnitine is required for beta-oxidation, it was suggested that decreased carnitine transporters, and hence reduced carnitine uptake, could lead to impaired fatty acid oxidation in intestinal epithelial cells, and to cell injury. We investigated this issue by examining the expression of the carnitine transporters OCTN2 and ATB0+, and butyrate metabolism in colonocytes in a rat model of IBD induced by trinitrobenzene sulfonic acid (TNBS). We found that Octn2 and Atb0+ expression was decreased in inflammatory samples at translational and functional level. Butyrate oxidation, evaluated based on CO2 production and acetyl-coenzyme A synthesis, was deranged in colonocytes from TNBS-treated rats. Treatment with carnitine-loaded liposomes corrected the butyrate metabolic alterations in vitro and reduced the severity of colitis in vivo. These results suggest that carnitine depletion in colonocytes is associated with the inability of mitochondria to maintain normal butyrate beta-oxidation. Our data indicate that carnitine is a rate-limiting factor for the maintenance of physiological butyrate oxidation in colonic cells. This hypothesis could also explain the contradictory therapeutic efficacy of butyrate supplementation observed in clinical trials of IBD.
D'Argenio
Giuseppe
G
Gastroenterology Unit, Department of Clinical and Experimental Medicine, University Federico II, Naples, Italy.
Calvani
Menotti
M
Casamassimi
Amelia
A
Petillo
Orsolina
O
Margarucci
Sabrina
S
Rienzo
Monica
M
Peluso
Ivana
I
Calvani
Riccardo
R
Ciccodicola
Alfredo
A
Caporaso
Nicola
N
Peluso
Gianfranco
G
D000595:Amino Acid Sequence; D026962:Amino Acid Transport System ASC / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D020148:Butyric Acid / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D050479:Neurotransmitter Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000074058:Solute Carrier Family 22 Member 5; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D026962:Amino Acid Transport System ASC; D008081:Liposomes; D050479:Neurotransmitter Transport Proteins; D027701:Organic Cation Transport Proteins; C115441:Slc22a5 protein, rat; C515774:Slc6a14 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D020148:Butyric Acid; D014302:Trinitrobenzenesulfonic Acid; D002331:Carnitine