Lipid News

The many layers of cholesterol regulation

Arun Radhakrishnan
By Arun Radhakrishnan
Oct. 1, 2017

Cholesterol levels in the membranes of animal cells are regulated carefully to remain within narrow limits. Regulation is carried out by a network of proteins that resides in the endoplasmic reticulum, or ER, and controls the two pathways by which cells obtain cholesterol: synthesis and uptake from circulating lipoproteins. The key proteins of this network include a cholesterol sensor and a transcription factor. The sensor is Scap, a polytopic ER membrane protein that binds membrane cholesterol. The transcription factor is a domain of another ER membrane protein called sterol regulatory element-binding protein, or SREBP.

Cholesterol accessibility at the surfaces of membranes rises sharply when its concentration exceeds a threshold, and plays a role in regulating the total cellular level and intracellular distribution of cholesterol. courtesy of Anna Sokolov and Arun Radhakrishnan​

When ER cholesterol is low, Scap initiates a series of molecular events that eventually release SREBP’s transcription factor domain into the cytosol so it can travel to the nucleus to upregulate genes for cholesterol synthesis and uptake. When ER cholesterol rises above a threshold, Scap binds cholesterol and undergoes a conformation change that blocks the processing of SREBPs. Thus, Scap spearheads a feedback mechanism that ensures rapid adjustments to changes in cellular cholesterol levels to ensure cholesterol homeostasis.

However, the cellular distribution of cholesterol poses a significant challenge to this feedback mechanism. Seventy to 90 percent of the cell’s cholesterol is located in the plasma membrane, or PM, whereas Scap is in the ER, which contains only about 1 percent of the cell’s cholesterol. If Scap is to execute its sensing function, the cholesterol-poor ER must be in constant communication with the cholesterol-rich PM so it can be notified promptly of changes in cholesterol levels. Without such a link, Scap would be blind to changes in cellular cholesterol. Indeed, disrupting this link through the use of a toxin that sequesters cholesterol in the PM results in a lowering of ER cholesterol even though PM cholesterol is unchanged. In response to this artificial induction, Scap activates SREBPs even though cellular cholesterol has not been depleted.

How are cholesterol levels in ER linked to those in PM? This process requires mechanisms to transport hydrophobic cholesterol across the aqueous cytosol and mechanisms to regulate these transport pathways. Cholesterol transport likely involves a combination of vesicular, nonvesicular and membrane contact site-mediated pathways, and remains poorly understood. We know a little more about how this transport may be regulated. Recent work has used soluble cholesterol-binding toxins to assay the exposure of cholesterol at the surface of purified PMs. These studies revealed that PM cholesterol was sequestered in the membrane bilayer and inaccessible to toxins until it exceeded a threshold concentration of about 35 mole percent of total PM lipids. Above this sharp threshold, PM cholesterol was accessible to bind to toxins. Sharp changes that have been observed for the exposure of PM cholesterol to the enzyme cholesterol oxidase may occur at similar thresholds.

It is tempting to speculate that intracellular cholesterol transport pathways are also sensitive to a sharp change in accessibility of cholesterol on the cytoplasmic leaflet of the PM, allowing for transport to ER to occur only after the PM’s cholesterol needs have been satisfied. How subthreshold levels of cholesterol are sequestered in the PM to prevent interactions with the intracellular transport machinery remains a mystery. We have learned a lot, but there are many more layers of cholesterol regulation yet to be revealed.

Arun Radhakrishnan
Arun Radhakrishnan

Arun Radhakrishnan is an assistant professor in the Department of Molecular Genetics, University of Texas Southwestern Medical Center.

Related articles

From the journals: JLR
Vaishnavi Muralikrishnan
From the journals: JLR
Lisa Learman & Laurel Oldach

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

St. Jude and maximizing the value of blood
Health Observance

St. Jude and maximizing the value of blood

June 14, 2021

The hospital is most renowned for passing along no costs to families. To facilitate this, the in-house capabilities of St. Jude are second to none. This includes the on-site blood donation facilities.

A balancing game with implications for neurodegenerative disease
Journal News

A balancing game with implications for neurodegenerative disease

June 8, 2021

The relationship between two proteins, one essential to mitochondrial fission and the other found in Alzheimer’s tissue, might hold the key to how disease alters the fission–fusion balance.

Can people vaccinated against COVID-19 still spread the coronavirus?
News

Can people vaccinated against COVID-19 still spread the coronavirus?

June 6, 2021

Preliminary evidence seems to suggest that someone who’s vaccinated is less likely transmit the virus, but the proof is not yet ironclad.

Addgene expands its collection into antibodies
News

Addgene expands its collection into antibodies

June 4, 2021

The reagent repository Addgene, known for distribution and quality control of plasmids for open science, is expanding into recombinant antibodies and nanobodies in partnership with NeuroMab.

Study reveals experimental targets for lymphoma research
Journal News

Study reveals experimental targets for lymphoma research

June 3, 2021

An enzyme previously linked to lymphoma development may have more functions than previously thought.

Exploring underappreciated molecules and new cities
Interview

Exploring underappreciated molecules and new cities

June 2, 2021

Neurochemist Xianlin Han has been an associate editor for the Journal of Lipid Research since 2019.