ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells

Abstract

In addition to sphingomyelin and ceramide, sugar derivatives of ceramides, hexosylceramides (HexCer) are the major circulating sphingolipids. We have shown that silencing of ABCA1 transmembrane protein function for instance in cases of loss of function of ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels. However, proteins involved in hepatic synthesis and egress of HexCer from cells is not well known although ABCA1 seems to be indirectly controlling the HexCer plasma levels by supporting HDL synthesis. In this study, we hypothesized that protein(s) other than ABCA1 are involved in the transport of HexCer to HDL. Using an unbiased knockdown approach, we found that ATP-binding cassette transporter protein C10 (ABCC10) participates in the synthesis of HexCer and thereby affects egress to HDL in human hepatoma Huh-7 cells. Furthermore, livers from ABCC10 deficient mice had significantly lower levels of HexCer compared to wild type livers. These studies suggest that ABCC10 partakes in modulating the synthesis and subsequent efflux of HexCer to HDL in liver cells.

Circulating Sphingolipids in Insulin Resistance, Diabetes and Associated Complications

“…The mechanisms by which sphingolipids generated at tissue level may efflux into lipoproteins or be transported to the liver for possible incorporation into lipoproteins, and the flux rate and half-life of plasma sphingolipids are mostly unknown. As previously described [ 19 , 20 , 21 ], plasma, ceramide, sphingomyelin, and hexosylceramide levels were found to be regulated by MTP and ABCA1; however, the mechanisms mediating the incorporation of lactosylceramide, dihydroceramide, as well as sphingoid bases and their phosphates into lipoproteins and their transport to the plasma are not yet identified.…”

“…The results identified microsomal triglyceride transfer protein (MTP) and ATP-binding cassette family A protein 1 (ABCA1) as critical determinants of plasma sphingolipid levels, and showed that MTP could be involved in ceramide and sphingomyelin secretion, but not in their synthesis. It has been also shown that ABCA1 deficiency in humans and mice reduces plasma glucosylceramide levels [ 19 ], and that ABCC10 may play a role in the synthesis and efflux of glucosylceramide to HDL particles [ 20 ].…”

Differential Regulation of Glucosylceramide Synthesis and Efflux by Golgi and Plasma Membrane Bound ABCC10

“…We recently reported that ABCC10 plays an important role in the synthesis and secretion of GlcCer [ 18 ]. Budani et al [ 14 ] showed that multiple ABC transporters potentially act as GlcCer flippases and differentially control GSL biosynthesis.…”

“…Some of the GlcCer may be effluxed out of the cells to the media by ABCC10 ( Figure 8 A). Down-regulation of ABCC10 with siRNA [ 18 ] or inhibition with sorafenib or tamoxifen may decrease the flippase activity of ABCC10 on the Golgi membrane, causing a feedback inhibition of GCS, leading to reduction in GlcCer synthesis in the cells, as has been shown with other transporter proteins such as ABCA3, ABCA4, ABCB10, ABCA12, and ABCB1 [ 14 ]. We have previously shown that microsomal triglyceride transfer protein (MTP) enhances cellular cholesteryl esterification by relieving the product inhibition of ACAT enzymes by transferring the products from the enzymes’ active site onto the apoB-containing lipoproteins [ 42 ].…”

“…However, induction, downregulation, inhibition, or knockdown of ABCA1 in human hepatoma Huh-7 cells had no effect on GlcCer efflux to HDL [ 17 ]. Recently, we identified that ABCC10 plays a role in the synthesis and efflux of GlcCer in Huh-7 cells [ 18 ], and ABCA1 may indirectly affect plasma GlcCer levels by playing a role in the biogenesis of HDL. We hypothesized that ABCC10 may act as a flippase of GlcCer and, therefore, regulate its synthesis and efflux.…”