The Regulation of Hepatic Choline Transport

Abstract

Choline is an essential nutrient, in the liver it is a precursor necessary for the synthesis of phosphatidylcholine (PC) and is also required as a methyl donor towards the synthesis of betaine and later regeneration of S-adenomethionine (SAM). Choline deficiency is known to trigger the development of non-alcoholic fatty liver disease and affect mitochondrial homeostasis along with a myriad of methylation related regulatory mechanisms. Because of its importance in maintaining liver lipid and mitochondrial homeostasis, choline metabolism has been well characterized with the exception of its transport. The identification of choline transporters has only been recently discovered and because of this, relatively little is known about their expression and regulation. This study has established that choline transporter like proteins 1-5 (CTL1-5) is an intermediate affinity transport system responsible for ~80% of hepatic choline uptake with a smaller percentage accomplished through the low affinity organic cation transporter 1-3/N1-2 (OCT1-3/N1-2) transporters. SLC44A1 expression and choline incorporation have been shown to follow a 24 hour rhythmic trend suggesting the presence of a circadian regulatory mechanism. This finding is supported by the significant decrease in choline expression and aberrant pattern of choline incorporation discovered among rhythmic deficient BMAL-/- mice and through a bioinformatics analysis which revealed the existence of four REV-ERBα consensus sequences. Hepatic SLC44A1 expression and choline incorporation have also been shown to decrease with the onset of obesity. Choline uptake was also shown to decrease following treatment with the free fatty acid oleate. This work increases our knowledge of hepatic choline transport and demonstrates a link between the circadian rhythm and obesity with the hepatic CTL1 transporter.