LDL-cholesterol transport to the endoplasmic reticulum: current concepts

Abstract

Purpose of review: In this article, we summarize the present information related to the export of LDL-derived cholesterol from late endosomes, with a focus on Nieman-Pick disease, type C1 (NPC1) cholesterol delivery toward the endoplasmic reticulum (ER). We review data suggesting that several pathways may operate in parallel, including membrane transport routes and membrane contact sites (MCSs).

Recent findings: There is increasing appreciation that MCSs provide an important mechanism for intermembrane lipid transfer. In late endosome-ER contacts, three protein bridges involving oxysterol binding protein related protein (ORP)1L-vesicle associated membrane protein-associated protein (VAP), steroidogenic acute regulatory protein (StAR)D3-VAP and ORP5-NPC1 proteins have been reported. How much they contribute to the flux of LDL-cholesterol to the ER is currently open. Studies for lipid transfer via MCSs have been most advanced in Saccharomyces cerevisiae. Recently, a new sterol-binding protein family conserved between yeast and man was identified. Its members localize at MCSs and were named lipid transfer protein anchored at membrane contact sites (Lam) proteins. In yeast, sterol transfer between the ER and the yeast lysosome may be facilitated by a Lam protein.

Summary: Increasing insights into the role of MCSs in directional sterol delivery between membranes propose that they might provide routes for LDL-cholesterol transfer to the ER. Future work should reveal which specific contacts may operate for this, and how they are controlled by cholesterol homeostatic machineries.

FIGURE 1

Delivery of LDL-cholesterol to the plasma membrane and endoplasmic reticulum. Left: microscopic images of a cell protrusion showing the positioning of marker proteins Cherry-CD63 [highlighting late endosomes (LEs) and plasma membrane (PM)] and BFP-KDEL [highlighting endoplasmic reticulum (ER)]. Right: simplified schematic illustration of LDL-cholesterol delivery routes. Upon LDL endocytosis, LDL-cholesterol reaches multivesicular bodies (MVBs) and LEs. LDL-cholesterol can reach the PM via a Rab8a/Myo5b/actin-dependent vesicular trafficking pathway or potentially via membrane contact sites (MCSs) via other organelles, such as peroxisomes (P). PM cholesterol can be transported to the ER, potentially involving PM-ER MCSs. LDL-cholesterol can also reach the ER via vesicular trafficking, involving retrograde transport via the Golgi, or may undergo direct transport between LE and ER at MCSs. These MCSs remain to be molecularly characterized but may involve sterol binding proteins (see Table 1). BFP-KDEL was a gift from Gia Voeltz [44].

Box 1

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