Untargeted Metabolomics Analysis of ABCC6-Deficient Mice Discloses an Altered Metabolic Liver Profile.

Loss-of-function mutations in the transmembrane ABCC6 transport protein cause pseudoxanthoma elasticum (PXE), an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. Untargeted metabolomics using liquid chromatography-mass spectrometry was employed to inspect liver cytosolic extracts from mice with targeted disruption of the Abcc6 gene. Absence of the ABCC6 protein induced an altered profile of metabolites in the liver causing accumulation of compounds as more features were upregulated than downregulated in ABCC6-deficient mice. However, no differences of the identified metabolites in liver could be detected in plasma, whereas urine reflected some of the changes. Of note, N-acetylated amino acids and pantothenic acid (vitamin B5), which is involved in acetylation reactions, were accumulated in the liver. None of the identified metabolites seems to explain mineralization in extrahepatic tissues, but the present study now shows that abrogated ABCC6 function does cause alterations in the metabolic profile of the liver in accordance with PXE being a metabolic disease originating from liver disturbance. Further studies of these changes and the further identification of yet unknown metabolites may help to clarify the liver-related pathomechanism of PXE.

Vitamin B12 transport from food to the body's cells--a sophisticated, multistep pathway.

Vitamin B(12) (B(12); also known as cobalamin) is a cofactor in many metabolic processes; deficiency of this vitamin is associated with megaloblastic anaemia and various neurological disorders. In contrast to many prokaryotes, humans and other mammals are unable to synthesize B(12). Instead, a sophisticated pathway for specific uptake and transport of this molecule has evolved. Failure in the gastrointestinal part of this pathway is the most common cause of nondietary-induced B(12) deficiency disease. However, although less frequent, defects in cellular processing and further downstream steps in the transport pathway are also known culprits of functional B(12) deficiency. Biochemical and genetic approaches have identified novel proteins in the B(12) transport pathway--now known to involve more than 15 gene products--delineating a coherent pathway for B(12) trafficking from food to the body's cells. Some of these gene products are specifically dedicated to B(12) transport, whereas others embrace additional roles, which explains the heterogeneity in the clinical picture of the many genetic disorders causing B(12) deficiency. This Review describes basic and clinical features of this multistep pathway with emphasis on gastrointestinal transport of B(12) and its importance in clinical medicine.