Is There Anything Fat Can’t Do?

Last week we talked about fat, but fats are just one of the many lipids in living organisms. Lipids are the fourth of our four biomolecules; we’ve already discussed proteins, carbohydrates and nucleic acids. Lipids may be last, but they're certainly not least.

Basically, all fats are lipids, but not all lipids are fats. The players are varied both in structure and function. Fats are three fatty acids + glycerol, but lipids are any of a group of organic compounds, including fats, oils, waxes, sterols, and triglycerides. The unbroken rule is that all lipids are insoluble in water, soluble in nonpolar organic solvents, and oily to the touch.

This cartoon shows the plasma membrane of a typical cell. Water on the outside (exoplasmic face) and inside (endoplasmic face) next to the outer and inner leaflets of the bilayer. The hydrophobic and hydrophilic regions are set by the structure of the phospholipid, shown bigger on the right. The little + shows where the head molecule is, and the _ sign is where the phosphate is (hence the name phospholipid). The two fatty acid tails can be the same or different, here they are same (count the carbons in grey).

  

All lipids are made from fatty acids – although only about half are recognizable as fatty acid products. Fats are a glycerol molecule with three fatty acids attached, but phospholipidsare usually a glycerol with just two fatty acid chains. The third glycerol position is taken by the head molecule of the phospholipid. The common heads are choline, ethanolamine, and the amino acid serine. Yet another non-protein function of an amino acid.

Phospholipids spontaneously form lipid bilayers (see picture) and spherical hollow spheres, which are perfect for making cell membranes. The heads are hydrophilic (hydro = water, and philia = loving) while the fatty acid tails are hydrophobic (phobia = fear). This makes for a potent cell membrane, keeping the large water-soluble molecules inside the cell because they won’t pass through the hydrophobic tail region. Notice how the two hydrophilic regions face water, while the two hydrophic portions of each layer hide on the inside.

The cell membrane isn’t made of only lipids; there are thousands of different proteins that perform many functions – signaling, receiving chemical messages, acting as channels and transporters for different molecules that can’t make it through the membrane on their own. There are also some other lipids in the membrane that we will talk about in a minute.

Sphingosine is the backbone for sphingolipids, but it has other functions as well. S1P stands for sphingosine-1- phosphate, and important molecule in membrane signaling. You can see some of the players here, Akt, Rac, Src and other second messengers are phosphorylated and phosphorylate other molecules to pass the message along. Here the message is about whether the cell should move (migrate). The shown pathways are just the start of the response.

Of course there are exceptions within the phospholipids. Triglycerides and phospholipids are built on a glycerol backbone, but sphingolipids are based on a molecule called sphingosine. Sphingomyelin (the head is choline) is considered a phospholipid because it functions similarly, but it is structurally different and has only one fatty acid tail.

Sphingolipids also sit in membranes, but they are usually asymmetric. This means that there are usually more of these in the outer layer of the phospholipid bilayer, also called the outer leaflet. From here they participate in a lot of the signaling through the membrane and in protecting the membrane from damage. When the cell is damaged and needs to commit suicide (apoptosis), divide, reduce its function (senescence), or differentiate (change what type of cell it is), part of the signaling will go through the sphingolipids.

The fatty acids that make of the hydrophobic tails of phospholipids and sphingolipids can vary; even  the two fatty acids on a single phospholipid can be different. One of the most common phospholipids is DPPC – dipalmitoylphosphatidylcholine. This means the head molecule is phosphocholine, the backbone is glycerol, and the two fatty acids are both palmitic acid, a fatty acid with no double bonds (saturated) and a chain of 16 carbons.

Palmitic acid itself is designated as C16:0, meaning it has 16 carbons and zero double bonds; oleic acid is C18:1, and so on. Fatty acids of two to 36 carbons have been found in nature, with many variations as to the number of double bonds.

These are typical fatty acids found in most cells. Palmitic is one of the most common in the fatty acids of membranes. You see that the more double bonds (all cis- here) they have, the number after the colon, the more they bend. Arachidonic acid is a veritable contortionist. Erucic is one of the lesser common fatty acids, it is important in Lorenzo’s oil, a treatment for adrenoleukodystrophy, and the subject of the movie of the same name.

Oddly, fatty acids with an odd number of carbons are rare in mammals. Our system of producing fatty acids works by adding carbons two at a time, so the products are usually even numbered. Breaking down fatty acids is also done two at a time; oxidation of odd chain fatty acids requires three extra enzymatic steps. That’s a waste of resources, so we stick to even numbers.

But there are exceptions. Ruminant animals have about 5% odd chain fatty acids, much more than other mammals. Why would this be?

What if I told you that bacteria and plants have lots of odd chain fatty acids? Ruminants (cows and such) have lots of bacteria in their numerous stomachs; the microbes help break down the plant cellulose of the ruminants’ plant diet. Naturally, some of these odd number FAs get incorporated into the animals’ tissues. A 2012 review pieced together the evidence so that changing levels of odd chain fatty acids in the stomachs of cows could be used to predict rumen health. More of C17:0 for instance, might indicate a rumen acidosis.

Free fatty acids (FFA) are attached to nothing, and rarely found on their own. In fact, they can be toxic in high concentrations. However, when we break down triglycerides to burn for energy, the fatty acids are released as FFA, so a low level can be found in the blood. Does that mean it's bad to lose weight too quickly; could you release so much FFA that you toxify yourself? Exercise might be dangerous!

Free fatty acids are also referred to as unesterified fatty acids. It is an ester bond that attaches them to the glycerol molecule in a triacylglycerol (fat) molecule. Here is one pathway where they work to increase sugars in the blood (hyperglycemia). This is one way FFA are said to lead to obesity and type II diabetes. They also have effects on the insulin producing cells.

FFAs can be trapped in cells and membranes. FFAs are broken down through a process called lipid peroxidation, releasing free oxygen radicals that can damage the cell. This is thought to be important in development of obesity-related type II diabetes, since the insulin producing beta cells of the pancreas are targeted by FFAs. I don’t know why the FFAs target the beta cells – that could be your ticket for a Nobel.

Here comes an exception - heart and skeletal muscle actually preferto use FFAs as energy sources as compared to glucose! This may be due to the higher energy storage potential of fatty acids, these high energy demanding tissues can get more bang for their buck by using fatty acids. The difference is that these fatty acids are usually bound to albumin in the blood, so they are not toxic like free fatty acids.

We humans can make most of the fatty acids they need. But, as with amino acids, there are a couple that we must get from our diet. These are the essential fatty acids, linolenic (C18:3n-3) and linoleic (C18:2n-6). The terminology is getting deep, but these are the omega three and omega 6 fatty acids. We can’t make double bonds beyond the #9-10 carbons in a fatty acid chain, so the omega fatty acids have to be brought on board by eating fish and plant oils (see the picture above).

Here are some good sources of essential fatty acids, the omega-3 and omega 6 fatty acids. Rapeseed and olives are among the vegetable oils that are high in essential fatty acids, as well as the oily fishes (salmon, herring, mackerel) and nuts. I never thought of eggs as particularly good sources, but there they are. Apparently hens raised on greens and insects have more essential fatty acids in their eggs as compared to hens fed grains.

Recently, evidence is piling up that omega 3 fatty acids are excellent for preventing and treating depression. A 2013 review indicates that omega-3’s are good for treating major depressive disorder. Another 2013 study showed that the number of self-reported depressive symptoms in American women are inversely proportional to the amount of omega-3 fatty acids consumed in their diet. Eat fish to be happy!

The essential fatty acids + arachidonic acid (20:4n-6) are also important for constructing another form of lipid – the eicosanoids(including the prostaglandins, thromboxanes and prostacyclins and leukotrienes). However, eicosanoids are so modified that it would be hard to tell they were based on fatty acids. These lipids are essential for the function of the immune system, including controlling inflammation, clotting, pain, and fever.

The exception to this is the endocannabinoids. These molecules do work in inflammation, but also have a lot to do with regulating mood and behavior. This may be why essential fatty acids are important in treating depression. You have probably noticed that the word (and structure) of the endocannabinoid bears resemblance to the active ingredient in marijuana – tetrahydrocannabinol (THC). This may also reflect their mood altering capabilities.

The final group of lipids we will talk about are the sterols. These (and the cardiolipins) are based on ring structures (see picture), having started out as fatty acids. The functions of sterols are many and diverse. They serve in hundreds of different signaling systems as a major class of hormones (like the sex hormones testosterone and estradiol and the metabolic hormone cortisol).

On the top you can see how the cholesterol (yellow) breaks up the monotony of the phospholipids. The space makes it easy for proteins and lipids to flow – hence the fluid mosaic model. This is shown better in the bottom cartoon. The #2 shows a lipid raft, made with phospholipids with longer tails, and similar proteins to do similar functions. These rafts can move around to where they are needed on the surface, break up and reform later, all because the elements of them are fluid. Thank you cholesterol.

Cholesterolis also a sterol lipid. I know that cholesterol gets a bad rap, but you don’t own a single cell that can survive without it. It's the "other lipid" in the lipid bilayer, serving to maintain the fluidity of the membrane. Part of the fluid mosaic model, cholesterol inserts itself into the bilayer and keeps the chains of the phospholipids from becoming entangled. They also work with the proteins to allow for movement around the cell surface.

So those are the lipids - definitely necessary for long-term energy storage, but also crucial for cell integrity and nearly every other function in an organism. Just to highlight this, let’s look at two very different functions of lipids.

Your brain just don’t work good without lipids! Many of your neurons have a lipid coating around them called myelin. The electrical impulse travels down the neuron in an unmyelinated neuron (grey matter), but can jump from the gap to gap (called nodes) in a myelinated neuron (white matter). This makes for much faster processing of neural signals, and is the only reason we can function at the level we do.

Trouble with lipid storage and function (called lysosomal lipid storage diseases) will mess with myelination. Diseases like Gaucher’s disease and Niemann-Pick both have myelination problems, and can result in severe mental retardation. These are inherited diseases, but there is an exception. Poisoning with swainsonine (from a plant called locoweed) can also result in poor lipid storage and function. It can drive cows mad (get it - locoweed), but is also a promising cancer drug.

Sphingomyelin makes up much of the myelin sheath around the neurons – the name makes sense now, right? The Schwann cell makes the myelin sheath by wrapping itself around the neural axon. The electrical impulse then jumps from node to node, making it much faster.. Not all neurons are myelinated, just the “white matter” of the brain. Look up white and grey matter.

Lastly, lipids control your genes. Lipid droplets in your cells interact with the histone proteinsthat control the packaging of the DNA. DNA wrapped around histones tightly is not open to be replicated or transcribed, so no genes there can be made into protein. But a 2012 study in fruit flies showed that lipid droplets are intimately associated with proper development. Lipid droplets serve as a reservoir of histones, which can be toxic when floating freely. If lipid droplets decrease, excess histones are free to wreak havoc, and the embryo dies. Still think fats are to be avoided?

Next week, let get into the holiday spirit by looking at the biology of snow. It saved Rudolph from being a meal for some predator!