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Multidrug permeases and subcellular cholesterol transport

Nature Reviews Molecular Cell Biology volume 2, pages 657–668 (2001)Cite this article

Key Points

  • The intercellular distribution and transport of cholesterol is a well-characterized process. However, the specific events that characterize the intracellular movement and distribution of cholesterol and other lipids are only poorly understood.

  • Low-density lipoprotein (LDL) particles carry cholesterol and other lipids from the liver to peripheral tissues, whereas high-density lipoprotein (HDL) particles facilitate the transport of these lipids from peripheral tissues back to the liver.

  • LDL particles are endocytosed and broken down in the endosomal–lysosomal system. Free cholesterol and presumably other lipid components of these particles exit the endosomal system and are transported to the plasma membrane.

  • From the plasma membrane, cholesterol can be transported to the endoplasmic reticulum and other intracellular sites. In addition, a plasma membrane ABC-type transporter facilitates the efflux of cholesterol and phospholipids onto HDL particles.

  • More than 10 ABC-type transporters are now known to facilitate the movement of cholesterol and other lipids across membrane bilayers. Their defective activities are associated with several diseases, exemplified by defects in the ABCA1 transporter that was recently shown to cause Tangier disease.

  • A member of a second family of transporters (RND), which depend on a proton motive force gradient for their function, was recently shown to reside in late endosomes where it facilitates lipid exit from this compartment. The defective action of this protein, NPC1, causes NPC1 disease, an autosomal-recessive lipidosis.

  • Recently, two other proteins, MLN64 and NPC2 were shown to reside in the endosomal–lysosomal system and might be involved in cholesterol and other lipid efflux from this system.

  • Increasing our understanding of the function of ABC and RND transporters in mammalian cells and their involvement in lipid transport and homeostasis should reveal the mechanisms of subcellular lipid movement and homeostasis, and should add to our understanding of disease pathogenesis when these transporters malfunction.

Abstract

Studies of Niemann–Pick C (NPC) and Tangier diseases have led to the identification of the causative genes, NPC1 and ABCA1, respectively. Characterization of their protein products shows that NPC1 and ABCA1 are permeases that belong to two different superfamilies of efflux pumps, which might be important in subcellular lipid and cholesterol transport.

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Figure 1: The structure of low- and high-density lipoprotein particles.
Figure 2: Main routes of intracellular cholesterol movement.
Figure 3: Cholesterol products.
Figure 4: Topology of ABCA and RND-type permeases.
Figure 5: Sterol-regulatory-element-binding proteins.
Figure 6: Cholesterol movement facilitators.
Figure 7: The Hedgehog–Patched–Smoothened pathway.

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Acknowledgements

I apologize for the omission of many outstanding papers that could not be cited or discussed owing to space limitations.

Author information

Authors and Affiliations

  1. Departments of Human Genetics, Gene Therapy and Molecular Medicine, Box 1498, The Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, 10029, New York, USA

    Yiannis A. Ioannou

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Supplementary information

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DATABASE LINKS

LDLR

HMGCR

LRP1

APOE

ACAT

APOB

NPC1

NPC

CAV1

CAV2

CAV3

SR-B1

Tangier disease

inventory of ABC proteins

ABC1

TAP

CFTR

GCN20

White

VMAT1

VMAT2

ABCA7

APOA1

ABCA1

LXR

RXR

ABCG5

ABCG8

sitosterolaemia

PTC

SHH

Niemann–Pick C1-like 1

HE1

NPC2

MLN64

STAR

Indian hedgehog

Desert hedgehog

FURTHER INFORMATION

Ioannou lab

Glossary

LOW-DENSITY LIPOPROTEIN RECEPTOR

(LDLR). A plasma-membrane receptor found on most mammalian cells. Responsible for the salvaging of cholesterol from circulation through the endocytosis of LDL particles.

LIPOPROTEINS

Particles such as LDL and HDL, found in the blood circulation, which carry lipids from the liver to peripheral tissues and back. These particles have a hydrophobic core containing triglycerides and cholesterol esters surrounded by a phospholipid and protein coat, composed of different apolipoproteins.

CLATHRIN-COATED VESICLE

Vesicles that bud off the plasma membrane or the trans-Golgi network. They have a characteristic protein coat, made up of clathrin triskelions.

GLYCOSYLPHOSPHATIDYL-INOSITOL (GPI)-ANCHORED PROTEINS

Proteins found predominantly at the plasma membrane, attached to the lipid bilayer through a hydrophobic anchor, consisting of the two-fatty-acid-chain lipid, glycosylphosphatidylinositol.

STEROL REGULATORY ELEMENT

A consensus sequence found in the promoter regions of several genes. The element is recognized by specific transcription factors that stimulate transcription when cellular sterol or fatty acid levels are low.

HIGH-DENSITY LIPOPROTEIN PARTICLES

(HDLs). Differ from LDLs in the composition of their hydrophobic core and the apolipoprotein composition of their coat.

ABC-TYPE TRANSPORTER

A type of transport protein that contains a consensus sequence known as the ATP-binding cassette.

WALKER A AND WALKER B MOTIFS

Protein motifs that form the nucleotide-binding site of an ABC domain. Walker A has the consensus GE-VALVGPSGSGKSTLL and Walker B the consensus ILLLDEPTSALD. (bold amino acids are invariant.)

PERMEASE

A membrane transporter, also known as a carrier protein or a transporter.

ANTIPORTS, SYMPORTS AND UNIPORTS

Uniports transport their substrate across a membrane. Coupled transporters couple the transport of their substrate to the transfer of a second solute, either in the same direction (symports) or in the opposite direction (antiports).

PROTON-MOTIVE FORCE

(PMF). The force generated across a membrane by the unidirectional transport of protons across a membrane. Both the membrane potential Δψ and the pH gradient ΔpH can contribute to this force.

APOLIPOPROTEIN A-1 (APOA1)

One of the apolipoproteins found predominantly in the coat of HDL particles.

LIPIDOSIS

Storage of various lipids in the lysosomal system is the common phenotype for this group of lysosomal storage diseases.

HEPATOSPLENOMEGALY

An enlargement of the liver and spleen seen in several lysosomal storage diseases.

LAMP-POSITIVE ORGANELLES

Organelles that contain the lysosome-associated membrane protein. Labels lysosomes.

RAB7-POSITIVE

Organelles that contain Rab7, a small GTPase found predominantly in late endosomes.

BODIPY

Trade name for a family of fluorophores that span the visible spectrum, and are used to label proteins, nucleotides, lipids and other molecules.

PERINUCLEAR VESICLES

Vesicular structures that are seen surrounding the nucleus. Usually indicative of lysosomes.

MANNOSE 6-PHOSPHATE MODIFICATION

A phosphate modification of the carbohydrate moieties of proteins destined for the endosomal–lysosomal system. This modification is recognized by the mannose 6-phosphate receptor in the trans-Golgi network, which captures these proteins and transports them to late endosomes.

YIN–YANG-1-BINDING SITE

A consensus sequence found in the promoter region of several genes. In the context of a sterol regulatory element, it acts as a negative regulator of transcription.

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Ioannou, Y. Multidrug permeases and subcellular cholesterol transport. Nat Rev Mol Cell Biol 2, 657–668 (2001). https://doi.org/10.1038/35089558

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  • DOI: https://doi.org/10.1038/35089558

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