Abstract
ABCB4/MDR3 is located in the canalicular membrane of hepatocytes and translocates PC-lipids from the cytoplasmic to the extracellular leaflet. ABCB4 is an ATP-dependent transporter that reduces the harsh detergent effect of the bile salts by counteracting self-digestion. To do so, ABCB4 provides PC lipids for extraction into bile. PC lipids account for 40% of the entire pool of lipids in the canalicular membrane with an unknown distribution over both leaflets. Extracted PC lipids end up in so-called mixed micelles. Mixed micelles are composed of phospholipids, bile salts, and cholesterol. Ninety to ninety-five percent of the phospholipids are members of the PC family, but only a subset of mainly 16.0-18:1 PC and 16:0-18:2 PC variants are present. To elucidate whether ABCB4 is the key discriminator in this enrichment of specific PC lipids, we used in vitro studies to identify crucial determinants in substrate selection. We demonstrate that PC-lipid moieties alone are insufficient for stimulating ABCB4 ATPase activity, and that at least two acyl chains and the backbone itself are required for a productive interaction. The nature of the fatty acids, like length or saturation has a quantitative impact on the ATPase activity. Our data demonstrate a two-step enrichment and protective function of ABCB4 to mitigate the harsh detergent effect of the bile salts, because ABCB4 can translocate more than just the PC-lipid variants found in bile.
Highlights
Supplementary key words adenosine 5′-triphosphate binding cassette transporter fatty acids adenosine 5′-triphosphatase activity bile ATP binding cassette subfamily B member 4
This membrane forms a meshwork between hepatocytes, which are connected via tight junctions, and several adjacent hepatocytes lead to the formation of the small bile duct [1,2,3]
Cholesterol is transported by ABCG5/G8 [9, 10], a heterodimer consisting of two half-size ABC transporters ABCG5 and ABCG8
Summary
To reduce the detergent action of these bile acids, the other two ABC transporters translocate additional compounds to intercept free bile salts in so-called mixed micelles. They consist mainly of phospholipids, cholesterol, and the bile salts. Considering the detergent action of bile salts and the fact that PC lipids exclusively are solubilized from the extracellular leaflet, it is counterintuitive that bile salts discriminate between lipids of different acyl chain composition [22] and favorably extract lipids independently of their headgroup [16] In such a scenario, ABCB4 translocates every PC-lipid variant presented to create a diverse pool of PC lipids in the outer leaflet.
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