The next session was dedicated to lipid transport within and/or across the membrane. SHAILESH PATEL (Charleston, South Carolina, USA) spoke on the recent discovery of the relation between mutations in the ABCG5 and ABCG8 genes in patients with sitosterolemia. These two genes encode half-transporters (named sterolin-1 and sterolin-2, respectively). Clinical symptoms of sitosterolemia are tendon xanthomas, accelerated atherosclerosis particularly affecting males at young age, hemolytic episodes, and arthritis and arthralgias. The hallmark biochemical feature of the disease is the elevated concentration of plant sterols in plasma. In different patients with this rare inherited disorder mutations were found in either the ABCG5 or the ABCG8 gene. This, together with the knowledge that several other ABC half-transporters dimerize into functional pumps, has given rise to the hypothesis that ABCG5 and ABCG8 are obligatory partners in a plant sterol pump. It is of importance to note that both genes are expressed in liver as well as in the intestine. Hence, the current hypothesis is, that in the gut the transporter couple extrudes plant sterols that enter the epithelial cells back into the gut lumen. The small amount of plant sterols that do enter the body are then efficiently pumped into bile by ABCG5 and ABCG8 in the canalicular membrane. Because these patients also have hypercholesterolemia, it is the hypothesis that this transporter couple also translocates cholesterol to some extent. However, it remains to be determined to what extent this transporter determines enteral absorption as well as biliary secretion of cholesterol. The locus has a very peculiar structure in that the two genes lay head-to-head on chromosome 2p21. Although the promoter of this gene pair has not been identified, yet it is clear that they are coordinately expressed and induced by the nuclear receptor LXR. GERD SCHMITZ (Regensburg, Germany) spoke about ABCA1, the expression of which is induced by cholesterol as is the case for a number of other ABC transporter genes of the A subfamily, such as ABCA3 and ABCA7. Mutations in the ABCA1 gene cause a complete lack of high-density lipoprotein (HDL; Tangier disease). The molecular function of ABCA1 in the assembly of nascent HDL is still unclear. He reported that, in addition to induction by the oxysterol-sensitive nuclear receptor LXR, ABCA1 transcription is repressed by the zinc finger protein ZNF202. The later transcription factor is located in a hypoalphalipoproteinemia locus on chromosome 11q23. In collaboration with the group of B. Sarkadi, G. Schmitz's lab analyzed ATP binding and ATPase activity in membranes from Sf9 cells expressing ABCA1. While they could observe ATP-binding properties of the protein, they were unable to measure ATPase activity, which led Gerd Schmitz to the assumption that ABCA1 functions as an ion (potassium) channel regulator rather than as a lipid translocator. Via this function ABCA1 might regulate the intracellular trafficking of vesicles to and from the plasma membrane. This function would be analogous to that of SUR in its complex with the potassium channel KIR6.2. ALBERT K. GROEN (Amsterdam, The Netherlands) spoke about the mechanism of biliary lipid transport. Phospholipid secretion involves phosphatidylcholine translocation by MDR3 P-glycoprotein (P-gp), but it is still unclear whether other gene products are involved in this complex process. When it was discovered that ABCA1 is involved in cholesterol transfer from cells to nascent HDL it was an interesting candidate for catalysis of cholesterol secretion into bile. Analysis of cholesterol secretion into bile of Abca1-/- mice demonstrated, however, that Abca1 plays no role in this process. In addition, the surprising observation was made that reverse cholesterol transport from peripheral tissues to the liver is not impaired in these knockout mice, indicating that the role of HDL in this process is overestimated. At least, in the absence of HDL in mice, reverse cholesterol transport is achieved via different pathways. Albert Groen reported that Abcg5 expression under conditions of different biliary cholesterol transport correlated well with the extent of cholesterol secretion into bile, which suggests that this gene product is involved.
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