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Mechanisms and regulation of cholesterol homeostasis

Abstract

Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification — a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.

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Fig. 1: Major pathways of cholesterol metabolism in a polarized cell.
Fig. 2: Mechanisms regulating cholesterol biosynthesis.
Fig. 3: Mechanisms regulating cholesterol uptake.
Fig. 4: Mechanisms regulating cholesterol efflux and esterification.

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Acknowledgements

The authors thank Lu-Yi Jiang and Yun-Feng Li for drafting the original figures. Work from the B.-L.S. laboratory is supported by grants from the National Natural Science Foundation of China (91753204, 31600651, 31690102, 91857000 and 31771568) and the Ministry of Science and Technology of China (2016YFA0500100 and 2018YFA0800700).

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J.L. and B.-L.S. wrote the Review and H.Y. revised it.

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Correspondence to Bao-Liang Song.

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Nature Reviews Molecular Cell Biology thanks N. Ridgway and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Sterols

A subgroup of steroids with a hydroxyl group at the C-3 position of the A-ring. A steroid is a biologically active organic compound with four rings (A–D) arranged in a specific molecular configuration.

Sphingolipids

A class of lipids with a polar head group and two non-polar tails. The core of a sphingolipid is an amino alcohol called sphingosine.

Glycosylphosphatidylinositol-anchored proteins

Proteins with glycosylphosphatidylinositol (GPI) attached at the C-termini. The GPI anchor is a unique mode of protein binding to the plasma membrane.

Oxysterols

The oxidized derivatives of cholesterol.

Bile acids

The hydroxylated steroids which are amphipathic and synthesized from cholesterol in the liver. Bile acids are secreted into the intestine where they play an important role in emulsifying dietary lipids to facilitate their absorption.

Niemann–Pick type C1

(NPC1). A large (1278 amino acids in humans), 13-pass transmembrane protein that binds cholesterol with the 3β-hydroxyl group and the tetracyclic ring of cholesterol buried and the iso-octyl side chain exposed via the N-terminal domain. NPC1 is ubiquitously expressed and localizes on lysosomal membrane. Mutations in NPC1 cause 95% of NPC cases.

Chylomicrons

The triglyceride-rich lipid particles in the blood and lymph that are solely produced by the intestine. Chylomicrons deliver lipids to the liver and extrahepatic tissues. After depletion of their triglycerides by the extrahepatic tissues, chylomicrons become chylomicron remnants that are cleared by the liver.

Very-low-density lipoproteins

(VLDLs). The triglyceride-rich lipid particles in the blood that are produced by the liver. VLDLs enable fats and cholesterol to move within the water-based bloodstream. VLDLs are converted to intermediate-density lipoproteins and low-density lipoproteins in the bloodstream.

Low-density lipoproteins

(LDLs). The lipid particles enriched in cholesteryl esters. Each LDL particle contains a single apolipoprotein B-100 molecule and delivers lipids, mainly cholesterol, and vitamins to extrahepatic tissues, where it is taken up by an LDL receptor.

Apolipoprotein

(apo). A protein that binds lipids to form lipoproteins, which then transport lipids and fat-soluble vitamins in circulation.

COPII-coated vesicles

The membrane vesicles coated by coatomer II (COP II), which is a type of vesicle coat protein that facilitates the formation of transport vesicles from the endoplasmic reticulum (ER). COPII-coated vesicles exit from specialized regions of the ER membrane devoid of bound ribosomes, known as ‘ER exit sites’, and deliver their content to the Golgi.

Insulin-induced gene (INSIG) proteins

INSIG proteins, including INSIG1 and INSIG2, are integral membrane proteins of the endoplasmic reticulum that mediate sterol regulation of sterol regulatory element-binding protein cleavage-activating protein (SCAP) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase).

RING-finger ubiquitin ligases

The largest type of E3 ubiquitin ligases with the RING (really interesting new gene) finger domains that bind two zinc ions in a unique ‘cross-brace’ arrangement through a defined motif of cysteine and histidine residues.

SCF ubiquitin ligase complex

The complex that catalyses the ubiquitylation of proteins for degradation. The core components of the Skp, Cullin, F-box (SCF) complex include the scaffold protein Cul1, the RING-finger protein RBX1/ROC1 and the adaptor protein Skp1. The F-box protein (FBP) is the variable component determining substrate specificity. In most cases, FBPs recognize phosphorylated proteins.

Sirtuin 1

(SIRT1). Member of a family of proteins that act predominantly as NAD-dependent deacetylases. There are seven sirtuins in mammals, SIRT1–SIRT7. Some sirtuins can remove various acyl lysine modifications from proteins.

ERKs

Widely expressed protein-serine/threonine kinases that are activated via the phosphorylation of tyrosine. Activation of ERK can affect cell proliferation, survival, apoptosis, motility, metabolism and differentiation.

AMPK

(AMP-activated protein kinase). A central regulator of energy homeostasis that is activated when the cellular ATP level is low. AMPK activation inhibits cholesterol and fatty acid synthesis.

Mevalonate

A product generated from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) by the action of HMG-CoA reductase. The mevalonate pathway in mammals leads to the synthesis of sterols, isoprenoids, dolichol, haeme, ubiquinione and so forth.

Isoprenoids

A class of naturally occurring organic compounds that are composed of two or more units of isoprene. They are synthesized in the mevalonate pathway in mammals.

Lanosterol

The first sterol intermediate in the mevalonate pathway consisting of 30 carbons. Lanosterol is synthesized by cyclization of squalene and can potently stimulate degradation of hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) without inhibiting the processing of sterol regulatory element-binding protein (SREBP).

ER-associated degradation

(ERAD). A surveillance system that clears misfolded proteins in the endoplasmic reticulum (ER) via ubiquitylation and proteasomal degradation.

Prenyltransferase

A class of enzymes that transfer prenyl moieties to acceptor molecules. They are responsible for menaquinone and ubiquinone biosynthesis, or protein modification called prenylation that is the covalent linkage of a lipid consisting of three or four isoprene units to a thiol of a cysteine side chain.

Geranylgeraniol

A diterpene alcohol containing 20 carbons that is synthesized in the mevalonate pathway. Geranylgeraniol can be used to synthesize vitamins E and K, and to modify proteins in a process known as geranylgeranylation.

E2 enzyme

Also known as ubiquitin-conjugating enzyme. E2 enzymes perform the second step in the ubiquitylation reaction. Through the series of reactions of E1, E2 and E3, cellular proteins are linked to ubiquitin.

Bile canaliculi

Thin tubes formed by intercellular space between hepatocytes. They carry biles towards the interlobar bile ducts.

Endocytic recycling compartment

(ERC). An intracellular cholesterol-rich site composed of a mixture of individual and interconnected vesicles and tubules near the microtubule-organizing centre. The ERC is RAB11a positive and regulates vesicular recycling to the plasma membrane.

Flotillins

A family of two ubiquitously expressed, membrane-associated proteins, namely, flotillin 1 and flotillin 2. They play a role in forming cholesterol-rich membrane microdomains, endocytosis and signal transduction.

Gangliosides

A species of plasma membrane-concentrated lipids. Each ganglioside molecule is composed of a glycosphingolipid linked to one or more sialic acid.

Brush border

The apical plasma membrane consisting of an array of densely packed microvilli, which are tiny projections intended to increase the surface area for absorption.

Liver X receptors

(LXRs). The sterol-sensitive transcription factors that belong to the nuclear receptor family and are activated by oxysterols and desmosterol. LXRs promote cholesterol efflux mainly by upregulating ATP-binding cassette (ABC) subfamily A member 1 (ABCA1) and ABC subfamily G member 1 (ABCG1), ABCG5 and ABCG8. They also increase fatty acid synthesis by elevating sterol regulatory element-binding protein 1c (SREBP1c) expression.

Thyroid hormones

Two tyrosine-based, iodine-containing hormones produced by the thyroid gland. They participate in the regulation of metabolism and growth.

ARH

(Autosomal recessive hypercholesterolaemia). An adaptor protein that binds low-density lipoprotein receptor and mediates its endocytosis in hepatocytes and lymphocytes. Mutations in ARH cause an autosomal recessive form of hypercholesterolaemia.

NPC2

(Niemann–Pick type C2). A small (132 amino acids in humans), luminal protein that resides in late endosomes and lysosomes, and binds cholesterol with the iso-octyl side chain of cholesterol buried and the 3β-hydroxyl group exposed. Mutations in NPC2 cause 5% of NPC cases.

ESCRT complexes

(Endosomal sorting complexes required for transport). These protein complexes comprise multiple cytosolic subunits. They transport ubiquitylated cargo to cellular vesicles by promoting membrane budding into the endosomes to form multivesicular bodies, which eventually fuse with lysosome and cause degradation of the cargo.

Foam cells

Cells derived from macrophages that take up too much cholesterol from oxidized low-density lipoproteins and become laden with lipid droplets, giving them a foamy appearance. Foam cells promote the atherosclerotic plaque build-up and inflammation during atherosclerosis.

Lecithin:cholesterol acyltransferase

(LCAT). A lipoprotein-associated enzyme that transfers the fatty acid from the sn-2 position of phosphatidylcholine (lecithin) to cholesterol to form a cholesteryl ester.

Transintestinal cholesterol excretion pathway

A process of faecal excretion of plasma-derived cholesterol from the inside of enterocytes to the intestinal lumen.

Micelles

The spherical assembly of amphiphilic molecules dispersed in water solvent.

Immunological synapse

The interface formed between an antigen-presenting cell or target cell and a lymphocyte such as a T cell, B cell or natural killer cell.

Sitosterol

A plant sterol with a chemical structure very similar to that of cholesterol. Sitosterol is poorly absorbed by healthy individuals and may help to lower cholesterol in humans.

Retinoic acid

A metabolite of vitamin A1 (all-trans-retinol). Retinoic acid is a ligand of nuclear receptors RAR and RXR and regulates cell growth and differentiation.

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Luo, J., Yang, H. & Song, BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol 21, 225–245 (2020). https://doi.org/10.1038/s41580-019-0190-7

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