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Cholesterol: Friend Before Foe

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Text by Jeanne Garbarino, animation and images by Perrin Ireland.

Scientific American: Cholesterol from Alphachimp Studio Inc. on Vimeo.

Mention the word cholesterol in front of my grandmother and she’ll automatically clutch her chest and say a little prayer. It is because she, along with almost one-fifth of the American population over 20 years of age, is battling high blood cholesterol – a condition tightly linked to heart disease. As a means to try and curb these undoubtedly dangerous cholesterol levels, which are generally the result of a poor diet, various organizations such as the American Heart Association (AHA) have unleashed anti-cholesterol campaigns, ultimately demonizing this unknowing molecule.

Yes, when in excess, cholesterol can be very detrimental to your health and is often the culprit behind heart attacks and strokes. However, behind the seemingly dangerous exterior lies a molecule that is essential for human life.

In the accompanying animation, I touched upon some of positive aspects of cholesterol. Here, I'll talk about these aspects in greater detail, hopefully explaining why cholesterol is a vital component of a normal existence.

Cholesterol is an essential building block of cell membranes

Cells would be just a pile of goo if their contents weren’t somehow contained. Like a plastic bag, membranes help to keep all the important stuff in while keeping the other stuff out. The basic blueprint for cell membrane construction involves lipids (fats) and proteins, with specialized lipids called phospholipids acting as the major structural components. However, the integrity of this phospholipid frame is largely determined by the amount of cholesterol it contains.

To clearly illustrate how cholesterol affects cell membranes, knowing a little bit more about phospholipids would be helpful. Picture a phospholipid molecule as a tennis ball with two long strings attached to it. The tennis ball represents the head “phospho” group and each string represents a hydrocarbon tail. When these hydrocarbon tails exist in a saturated form, they are more ordered (think butter) whereas when hydrocarbon tails are unsaturated, they are more fluid (think olive oil).

If a cell membrane was made up of phospholipids with mostly saturated hydrocarbon tails, the membrane would be too stiff. On the other hand, if phospholipid hydrocarbon tails were primarily unsaturated, the membrane would be too fluid. Either situation is a problem since basic cellular function relies on a membrane that is sturdy enough to hold everything together but flexible enough to let the important stuff pass in and out.

Consider cholesterol to be the porridge ingredient that makes it taste just right. Cholesterol will interact with phospholipids and help to make sure that our cell membranes are the perfect consistency. This interaction keeps saturated phospholipid-rich membranes from becoming too rigid as well as keeping membranes with high levels of unsaturated phospholipids from getting too loose. Basically, in terms of membrane structure, cholesterol helps to prevent extremes.

Now excuse me if I am being overzealous, but cholesterol is truly nature’s perfect solution for controlling membrane fluidity - it gives cell membranes the structural integrity of a solid while simultaneously giving it the mobility of a liquid. Not surprisingly, cells will invest a large amount of energy in order to maintain very specific cholesterol levels in membranes, highlighting the value of cholesterol to cells and, of course, to the organism to whom those cells belong. This is just one of the variety of reasons why cholesterol is essential for life.

Cholesterol is fundamental during our development in the womb

We are constantly bombarded with dangerous statistics relating to high cholesterol levels, yet conditions arising from cholesterol deficiencies are far less known. In the 1990s, the importance of cholesterol during fetal development became more clear when scientists discovered a link between low cholesterol levels and Smith-Lemli-Opitz Syndrome (SLOS) – a disease characterized by poor growth, developmental delays, reduced mental function, and a range of physical malformations.

Due to a genetic defect, those afflicted with SLOS cannot complete the last step of cholesterol formation, explaining reduced cholesterol amounts. As discussed above, cholesterol is an important component of cell membranes. When cell number is quickly expanding, as is the case when developing in the womb, the pace of membrane formation is very rapid. This puts cholesterol in extremely high demand. Scientists link reduced cholesterol availability and the resulting compromised cell membrane integrity as one of the explanations for SLOS symptoms.

However, cholesterol plays more than one part in the baby-making play. Yes, it is important for membrane production, but it also has an unexpected role. Shortly after defective cholesterol formation was linked to SLOS, it was found that it is also essential for developmental patterning – the process that keeps our body parts in order, from our heads to our toes.

More specifically, scientists found that cholesterol becomes attached to a specific family of proteins called hedgehog proteins. (Yes, the naming of these proteins is associated with the Sega Genesis game of my youth – Sonic the Hedgehog.) These proteins help to determine the fate of cell - i.e. whether the cell will become a part of a finger versus part of a toe - and are indispensable for normal and healthy development.

When the attachment of cholesterol to hedgehog is prevented in mice, it messes up finger and toe formation. Through experimentation, scientists found that cholesterol helps to regulate how many hedgehog proteins get go to specific areas within the developing embryo. Without the addition of cholesterol, hedgehog proteins would spread too far, and this has a significant effect on formation in utero. In essence, cholesterol acts as the parole officer, making sure that the hedgehog protein doesn’t go beyond the proper jurisdiction.

This adds another obvious tick to the “reasons why cholesterol is important” checklist!

Cholesterol gives us balls

Well, sort of - and only for about 50% of the population. More accurately, cholesterol is the starting material for steroid hormones including testosterone, which helps to define the male gender.

You can recognize a steroid hormone by its structure, which is very similar to that of cholesterol. Like cholesterol, the signature feature of a steroid hormone is the specific arrangement of four rings. However, hormones differ form cholesterol by the side chain(s) coming off of this multi-ring structure.

In humans and other mammals, using cholesterol to make steroid hormones is officially termed steroidogenesis and the products of these reactions can be classified based on their general role in the body. As such, most steroid hormones can be placed under five categories:

The importance of cholesterol during steroidogenesis is exemplified by the potentially lethal disease congenital lipoid adrenal hyperplasia (CLAH), a very rare genetic disorder characterized by the inability to use cholesterol to make steroid hormones (and which has its own Facebook page!). This disease is caused by a defect in the transport of cholesterol into the steroid hormone-making area of the cell (mitochondria), and the inability to produce sex hormones has severe repercussions, including infertility and gender identity issues for males.

Once again, let’s give credit where credit is due…

We use cholesterol to make Vitamin D

To use sunblock or not to use sunblock – when it comes to vitamin D production, it is widely known that the sun plays a role. But, it is less well known that cholesterol is the precursor to this nutrient.

When we are talking about vitamin D in humans, what we really mean is Vitamin D3, also known as cholecalciferol. Cholesterol is not directly transformed into vitamin D; more specifically, cholesterol is first converted to a compound called 7-dehydrocholesterol. Then, upon exposure to ultraviolet radiation (UV light from the sun), the 7-dehydrocholesterol in our skin is transformed to vitamin D3.

Most people are familiar with vitamin D3 as an important factor for bone health. In fact, it is in this context that vitamin D was first identified. In the early 20th century, scientists discovered that cod liver oil, which is rich in vitamin D, could be used to treat dogs with rickets. And thus, the incidence of rickets in developed nations plummeted.

Thanks, cholesterol, for making it all possible.

And now, a personal statement

If our bodies were a high school and molecules were the students, cholesterol would certainly win the “most important for life” superlative. Well, maybe I am a little biased because without cholesterol, I wouldn’t have a job – at least, I wouldn’t have my current job. And that would be a bummer.

The whole purpose of this article was to shed light on the positive aspects of cholesterol, the molecule, despite its bad reputation. But, a word of caution – just because cholesterol is central to a number of biological processes (including many I did not discuss!) doesn’t mean it is all well and good. This molecule also got the “most likely to kill you if kept at high levels in your body” superlative.

So, the next time you hear about cholesterol, remember that it plays a significant role during life, and that can be good as well as bad.

Enormous thanks to Perrin Ireland, Diane Durand, Patricia Fonner, and the rest of the folks at Alphachimp Studio (http://www.alphachimp.com/)!!!

The views expressed are those of the author and are not necessarily those of Scientific American.

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