New imaging study reveals how saturated fatty acids damage cells

December 2, 2017, Columbia University
Saturated fatty acids build lipids that form 'frozen islands' (blue) in cell membrane (green). Credit: Nicoletta Barolini, Columbia University

In our increasingly health-conscious society, a new fad diet seems to pop up every few years. Atkins, Zone, Ketogenic, Vegetarian, Vegan, South Beach, Raw - with so many choices and scientific evidence to back each, it's hard to know what's healthy and what's not. One message, however, has remained throughout: saturated fats are bad.

A new Columbia University study reveals why.

While doctors, nutritionists and researchers have known for a long time that saturated fats contribute to some of the leading causes of death in the United States, they haven't been able to determine how or why excess saturated fats, such as those released from lard, are toxic to cells and cause a wide variety of -related diseases, while unsaturated fats, such as those from fish and olive oil, can be protective.

To find answers, Columbia researchers developed a new microscopy technique that allows for the direct tracking of fatty acids after they've been absorbed into living cells. The technique involves replacing hydrogen atoms on fatty acids with their isotope, deuterium, without changing their physicochemical properties and behavior like traditional strategies do. By making the switch, all molecules made from fatty acids can be observed inside living cells by an advanced imaging technique called stimulated Raman scattering (SRS) microscopy.

What the researchers found using this technique could have significant impact on both the understanding and treatment of obesity, diabetes and cardiovascular disease.

Published online December 1st in Proceedings of the National Academy of Sciences (PNAS), the team reports that the cellular process of building the cell from saturated fatty acids results in patches of hardened membrane in which molecules are "frozen." Under healthy conditions, this membrane should be flexible and the molecules fluidic.

The researchers explained that the stiff, straight, long chains of saturated fatty acids rigidify the and cause them to separate from the rest of the cell's membrane. Under their microscope, the team observed that those lipid molecules then accumulate in tightly-packed "islands," or clusters, that don't move much - a state they call "solid-like." As more saturated fatty acids enter the cell, those islands grow in size, creating increasing inelasticity of the membrane and gradually damaging the entire cell.

"For a long time, we believed that all is liquid-like, allowing embedded proteins to change their shape and perform reactions," said Principal Investigator Wei Min, a professor of chemistry. "Solid-like membrane was hardly observed in living mammalian cells before. What we saw was quite different and surprising."

Lipid molecules made from on the other hand bear a kink in their chains, Min said, which makes it impossible for these lipid molecules to align closely with each other as saturated ones do. They continue to move around freely rather than forming stationary clusters. In their movement, these can jostle and slide in between the tightly-packed saturated .

"We found that adding unsaturated fatty acids could 'melt' the membrane islands frozen by saturated fatty acids," said First Author Yihui Shen, a graduate student in Min's lab. This new mechanism, she said, can partly explain the beneficial effect of unsaturated fatty acids and how unsaturated fats like those from fish oil can be protective in some lipid disorders.

The study represents the first time researchers were able to visualize the distribution and dynamics of fatty acids in such detail inside living cells, Shen added, and it revealed a previously unknown toxic physical state of the saturated lipid accumulation inside cellular membranes.

"The behavior of saturated fatty acids once they've entered contributes to major and often deadly diseases," Min said. "Visualizing how are contributing to lipid metabolic disease gives us the direct physical information we need to begin looking for effective ways to treat them. Perhaps, for example, we can find a way to block the toxic lipid accumulation. We're excited. This finding has the potential to really impact public health, especially for lipid related diseases."

Explore further: Saturated fatty acids might directly damage heart

More information: Yihui Shen et al, Metabolic activity induces membrane phase separation in endoplasmic reticulum, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1712555114

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dogbert
not rated yet Dec 02, 2017
The technique involves replacing hydrogen atoms on fatty acids with their isotope, deuterium, without changing their physicochemical properties and behavior like traditional strategies do. By making the switch, all molecules made from fatty acids can be observed inside living cells by an advanced imaging technique called stimulated Raman scattering (SRS) microscopy.


Interesting, but how did the researchers determine that the observed activity of the modified fatty acids in cell membranes was simply the normal activity of fatty acids and not an artifact of the deuterium?

Deuterium is known to be toxic to mammals and to change cell membranes.
xponen
not rated yet Dec 02, 2017
Deuterium is known to be toxic to mammals and to change cell membranes.

But toxic in a form of water, probably because the free Deuterium in water couldn't replace Hydrogen ions (Protons) which organelle such as Mitochondria usually use to generate energy, I guess because it simply can't perform like a normal free Protons. However, bacteria can survive with Deuterium water and produce deutered molecules so it isn't universal Toxic if cell expect it.

The fat with deuteriums is called deutered molecules but I think human cell won't metabolise deutered molecule, just like Deuterium water can't be use because of incompatibility, but... a typical SATURATED FAT is already implicated for damaging cells by stressing the endoplasmic reticulum (ER) in human cell and this research simply visualise the possible way of it doing that; this research showed that it harden the membrane wall of ER. Trying to see if Deuterium is doing something else after this is out of the scope.
Shootist
3 / 5 (2) Dec 02, 2017
The Atkins diet has been around since 1975 or so. Hardly a "fad" diet.
avandesande2000
5 / 5 (1) Dec 03, 2017
You know if you expose those cells to a high concentration of salt they will explode? Yet without salt a human will quickly die. I didn't read this study but I highly doubt the conditions in any way resemble the way fats are actually digested and stored in the body. More junk science headlines!
submicron
not rated yet Dec 03, 2017
The paper is indeed about toxicity of excess saturated fatty acids and how unsaturated ones can balance it.

You know if you expose those cells to a high concentration of salt they will explode? Yet without salt a human will quickly die. I didn't read this study but I highly doubt the conditions in any way resemble the way fats are actually digested and stored in the body. More junk science headlines!

dogbert
not rated yet Dec 04, 2017
submicron,
The paper is indeed about toxicity of excess saturated fatty acids and how unsaturated ones can balance it.


But to do the study, the researchers added a toxic substance to saturated fatty acids (deuterium). You might expect that adding toxic substances to a fatty acid would cause that fatty acid to be toxic.

The study does not show that unadulterated saturated fat is toxic.
submicron
not rated yet Dec 04, 2017
submicron,
The paper is indeed about toxicity of excess saturated fatty acids and how unsaturated ones can balance it.


But to do the study, the researchers added a toxic substance to saturated fatty acids (deuterium). You might expect that adding toxic substances to a fatty acid would cause that fatty acid to be toxic.

The study does not show that unadulterated saturated fat is toxic.


Testing toxicity of 'unadulterated' saturated fatty acid is a very basic control experiment in their study. And it seems to be a well-established fact in the field of 'lipotoxicity'. By the way, deuterium is not that toxic because it is not a radioactive isotope.

I would not infer too much from this study because how our dietary fat get into our cells depends on many factors. This study is more like the consequence of fatty acids that already enter cells.
dogbert
not rated yet Dec 04, 2017
submicron,
Testing toxicity of 'unadulterated' saturated fatty acid is a very basic control experiment in their study. And it seems to be a well-established fact in the field of 'lipotoxicity'.


If they already had determined that saturated fatty acid is toxic, then why do the study?

It seems that the study was designed to show that saturated fatty acid is toxic, but since it was adulterated with a toxic substance, the results of the study are questionable.
submicron
5 / 5 (1) Dec 04, 2017

If they already had determined that saturated fatty acid is toxic, then why do the study?

It seems that the study was designed to show that saturated fatty acid is toxic, but since it was adulterated with a toxic substance, the results of the study are questionable.


It's like you know something kills the cell, but you want to know how and why it kills. That helps design better medicine, I think.

I meant they showed that deuterium did not affect the toxicity compared to normal fatty acid. From what I learnt in chemistry, deuterium is essentially the same as hydrogen and is pretty safe. Only very high dose of deuterium in water is toxic. It is much less toxic on other molecules.

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