Journal News

Plasma membrane is no barrier to free fatty acid

Nathalie Gerassimov
October 27, 2020

Our understanding of how long-chain fatty acids cross membranes is changing based on recent work by James Hamilton’s laboratory at Boston University and others. Their research shows that unlike nutrients such as glucose or amino acids, which require a transporter, fatty acids can diffuse spontaneously through protein-free lipid bilayers and cells’ plasma membranes.

A recent paper in the Journal of Lipid Research by Anthony Jay and colleagues reveals how molecules previously thought to inhibit fatty acid transport specifically, including sulfosuccinimidyl oleate, or SSO, fit the diffusion model.

Control of fatty acid entry into cells is difficult to visualize. Researchers often have used fatty acid metabolites that become trapped in the cell to infer transport by plasma membrane proteins. The Hamilton lab has focused on distinguishing transmembrane movement from metabolism.

The lab made a seminal discovery that transport of fatty acids across a bilayer can be followed by pH changes. They combined a fluorescent fatty acid reporter with phospholipid vesicles enclosing a pH-probe to measure absorption in real time. They showed that natural fatty acids can acquire a proton near the outer leaflet, leading to equilibrium between neutral and ionized forms. The net neutral fatty acid spontaneously diffuses across the bilayer and then releases the proton near the inner leaflet, reducing the internal pH. This energy-free diffusion has been termed the “flip-flop” mechanism.

JLR-schematic-762x423.jpg
James Hamilton/JLR
This schematic shows that (A) sulfosuccinimidyl oleate can flip-flop across the bilayer to enter cells, and (B) it can modify amino acids.

“Our studies also showed that all fatty acids studied … exhibit rapid flip-flop, and that this mechanism is reversible,” Hamilton said.

The researchers were excited by this finding but acknowledge that it does not exclude a role for proteins. Jay said, “If fatty acids can simply diffuse into cells, how could there be inhibitors of this transmembrane movement?”

The recent paper tests several proposed transport inhibitors, including the gold standard, SSO. Scientists had described SSO as a specific inhibitor of fatty acid entry into cells that acts on the fatty acid transporter CD36 without penetrating membranes. However, Hamilton’s team showed that SSO crosses membranes. Immunofluorescence using novel antibodies that bind SSO-linked fatty acids suggested that SSO modifies numerous proteins on the cell surface and interior, refuting the assumption of CD36 specificity.

The research informs nutritional considerations, Hamilton said. “Metabolism, and not the plasma membrane, controls the retention of fatty acids in cells, by trapping the fatty acids. Although membrane proteins may bind fatty acids or participate in metabolism, they cannot block diffusion in the surrounding bilayer.”

JLR-Res-617x460.jpg
James Hamilton/JLR
These image show immunofluorescence staining of amino acids modified with the fatty acid transporter CD36
and the fatty acid transport inhibitor sulfosuccinimidyl oleate. The insert on the right suggest that SSO staining is not
exclusive to CD36.

In fact, cells with and without CD36 exhibited the same diffusion, but CD36 increased the content of intercellular lipids.

For nutrition, Hamilton emphasized, “Healthy fatty acids such as omega 3 fatty acids need to enter cells readily, whereas unhealthy fatty acids, such as trans fatty acids, cannot be excluded from cells and need to be reduced in the diet.”

Hamilton’s lab is moving on to clinical trials using a high concentration of beneficial fatty acids to improve stroke and heart attack outcomes. Meanwhile, he recommends taking omega-3 supplements and eating more nuts.

Another interpretation

According to Maastricht University researchers Jan Glatz and Joost Luiken, the Hamilton lab’s results also could be interpreted as a step toward integration of the argument that fatty acids diffuse across the cell membrane and the view that the protein CD36 is required for fatty acid uptake. In a Letter to the Editors of the JLR, Glatz and Luiken lay out their view that CD36 may be helpful but not necessary for lipid uptake.

Nathalie Gerassimov

Nathalie Gerassimov is a postdoctoral researcher at the Carnegie Institution of Washington department of embryology.

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

Brain Injury Awareness Month 2021
Health Observance

Brain Injury Awareness Month 2021

March 01, 2021

In the U.S., about 2.8 million people sustain a traumatic brain injury annually. Learn about recent research on TBI-related dementia, dysfunctional mitochondria and other work powering the march toward better therapies.

The evolution of proteins from mysteries to medicines
Essay

The evolution of proteins from mysteries to medicines

February 27, 2021

An essay in observance of National Protein Day.

'Every experiment and every breakthrough matters'
Health Observance

'Every experiment and every breakthrough matters'

February 26, 2021

An interview with NYMC dean Marina K. Holz, who studies a rare disease that affects women of childbearing age.

Progeria: From the unknown to the first FDA-approved treatment
Health Observance

Progeria: From the unknown to the first FDA-approved treatment

February 25, 2021

Hutchinson–Gilford progeria syndrome is a rare, fatal genetic disease that causes premature aging.

Raising awareness and funding for Pompe disease
Health Observance

Raising awareness and funding for Pompe disease

February 25, 2021

Father-turned-advocate has founded multiple organizations to support families and search for better therapies for people with rare lysosomal storage disorder.

A novel approach to septic shock leads to a prospective new therapy
Journal News

A novel approach to septic shock leads to a prospective new therapy

February 23, 2021

A French research team finds new evidence supporting endotoxin removal for treating life-threatening inflammation.