Srinivas Sonne R, Prasad Puttur D, Umapathy Nagavedi S, Ganapathy Vadivel, Shekhawat Prem S
Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Nov;293(5):G1046-53. doi: 10.1152/ajpgi.00233.2007. Epub 2007 Sep 13.
L-carnitine is absorbed in the intestinal tract via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). Loss-of-function mutations in OCTN2 may be associated with inflammatory bowel disease (IBD), suggesting a role for carnitine in intestinal/colonic health. In contrast, ATB(0,+) is upregulated in bowel inflammation. Butyrate, a bacterial fermentation product, is beneficial for prevention/treatment of ulcerative colitis. Butyryl-L-carnitine (BC), a butyrate ester of carnitine, may have potential for treatment of gut inflammation, since BC would supply both butyrate and carnitine. We examined the transport of BC via ATB(0,+) to determine if this transporter could serve as a delivery system for BC. We also examined the transport of BC via OCTN2. Studies were done with cloned ATB(0,+) and OCTN2 in heterologous expression systems. BC inhibited ATB(0,+)-mediated glycine transport in mammalian cells (IC(50), 4.6 +/- 0.7 mM). In Xenopus laevis oocytes expressing human ATB(0,+), BC induced Na(+) -dependent inward currents under voltage-clamp conditions. The currents were saturable with a K(0.5) of 1.4 +/- 0.1 mM. Na(+) activation kinetics of BC-induced currents suggested involvement of two Na(+) per transport cycle. BC also inhibited OCTN2-mediated carnitine uptake (IC(50), 1.5 +/- 0.3 microM). Transport of BC via OCTN2 is electrogenic, as evidenced from BC-induced inward currents. These currents were Na(+) dependent and saturable (K(0.5), 0.40 +/- 0.02 microM). We conclude that ATB(0,+) is a low-affinity/high-capacity transporter for BC, whereas OCTN2 is a high-affinity/low-capacity transporter. ATB(0,+) may mediate intestinal absorption of BC when OCTN2 is defective.
左旋肉碱通过肉碱转运体OCTN2和氨基酸转运体ATB(0,+)在肠道中被吸收。OCTN2的功能丧失突变可能与炎症性肠病（IBD）有关，这表明肉碱在肠道/结肠健康中发挥作用。相比之下，ATB(0,+)在肠道炎症中上调。丁酸盐是一种细菌发酵产物，对溃疡性结肠炎的预防/治疗有益。丁酰左旋肉碱（BC）是肉碱的丁酸盐酯，可能具有治疗肠道炎症的潜力，因为BC既能提供丁酸盐又能提供肉碱。我们研究了BC通过ATB(0,+)的转运，以确定该转运体是否可作为BC的递送系统。我们还研究了BC通过OCTN2的转运。研究是在异源表达系统中使用克隆的ATB(0,+)和OCTN2进行的。BC抑制了哺乳动物细胞中ATB(0,+)介导的甘氨酸转运（IC(50)，4.6±0.7 mM）。在表达人ATB(0,+)的非洲爪蟾卵母细胞中，BC在电压钳条件下诱导了Na(+)依赖性内向电流。电流是可饱和的，K(0.5)为1.4±0.1 mM。BC诱导电流的Na(+)激活动力学表明每个转运周期涉及两个Na(+)。BC还抑制了OCTN2介导的肉碱摄取（IC(50)，1.5±0.3 microM）。BC通过OCTN2的转运是电生性的，BC诱导的内向电流证明了这一点。这些电流是Na(+)依赖性的且可饱和（K(0.5)，0.40±0.02 microM）。我们得出结论，ATB(0,+)是BC的低亲和力/高容量转运体，而OCTN2是高亲和力/低容量转运体。当OCTN2有缺陷时，ATB(0,+)可能介导BC的肠道吸收。
