Figure 10

Proposed molecular mechanisms underlying the dysregulations in cholesterol and lipoprotein metabolism in ABCC6-deficient PXE fibroblasts. In case of ABCC6-deficiency in the liver, the potential substrate(s) of ABCC6 is/are missing in the circulation (1). Hepatocytes might possess substitutional routes to prevent possible toxic substrate accumulations (e.g. biliary excretion by other ABC transporter/s). Insufficient substrate supply by the liver then induces substrate biosynthesis in ABCC6-deficient dermal fibroblasts (e.g. cholesterol biosynthesis) (2). Due to a functional loss of ABCC6, newly synthesized metabolites accumulate intracellularly (3) and might provide an additional trigger for dysregulations in cholesterol homeostasis in addition to insufficient hepatic substrate supply.