An Introduction to Cholesterol

Cholesterol… simply uttering its name elicits intense fear. This fundamental lipid molecule is found in all eukaryotic cells, the cells of nearly all animals, and some plants and algae. A molecule that has been vilified in the health space since the 50s when Ancel Keys first posed his diet-heart hypothesis.

So what is cholesterol?

In this post, we will briefly delve into the diverse range of properties and functions of this molecule with pivotal significance in cellular structure and hormonal synthesis, which forms a complex web of metabolic intricacies within the human body.

What is Cholesterol?

Cholesterol is the most common sterol molecule. Sterols are distinguished from other lipids by a four-carbon-ring structure which contributes to their versatility. Like phospholipids, cholesterol is an amphipathic molecule boasting a hydrophobic tail and hydrophilic head allowing it to interact with fats and water. Imagine a magnet with one end attracted to fats and the other to water and if reversed they would repel each other. Cholesterol constitutes a fundamental structural component of cell membranes and serves as a precursor for the biosynthesis of steroid hormones and bile acids.

Origins in Nature

Cholesterol is predominantly of animal origin and mostly absent in plant-based sources. Dietary intake from animal-derived products such as meat, poultry, and dairy serves as a primary source of exogenous (external) cholesterol, influencing the balance of endogenous (internal) production.

Synthesis in Humans

Endogenous cholesterol synthesis primarily occurs in the liver, a highly metabolic organ. The process involves a series of enzymatic reactions, governed by the HMG-CoA reductase enzyme, which acts as a rate-limiting step. This tightly regulated biosynthetic pathway ensures a homeostatic balance in cholesterol levels.

Key Functions

Cholesterol's functional repertoire extends beyond its role in cellular membranes. As a precursor molecule, it contributes to the synthesis of vitamin D3 which is almost structurally identical to cholesterol besides one open ring. It is also essential for the synthesis of hormones, including glucocorticoids, mineralocorticoids, and sex hormones. It acts as a modulator of membrane fluidity, influencing cellular signalling.

Transportation Through the Body

When your doctor tells you your “cholesterol is too high” what they are typically referring to is a suboptimal level of Low-Density Lipoprotein (LDL). Lipoproteins are molecular complexes of lipids and proteins that function as carriers of lipids like cholesterol and triglycerides in the bloodstream. They have a hydrophobic core containing lipids and a hydrophilic outer layer of proteins, enabling them to efficiently transport fats through the water-based environment of the blood. Functioning like a water taxi, these boats carry passengers (cholesterol) through the water (bloodstream) delivering cholesterol to destinations in the body without interacting with the surroundings.

Lipoprotein Classifications

As a hydrophobic molecule, cholesterol relies on lipoprotein carriers for transport. Low-density lipoprotein ferries cholesterol from the liver to peripheral tissues. High-density lipoproteins play a crucial role in reverse cholesterol transport, escorting excess cholesterol back to the liver for breakdown or removal. More specific classifications of lipoproteins include chylomicrons, the largest and least dense, designed to transport dietary triglycerides, Very Low-Density Lipoproteins (VLDL) and Intermediate-density lipoproteins (IDL), which transport liver-synthesised triglycerides, characterised by a higher lipid-to-protein ratio. Each component contributes uniquely to the intricate dance of cholesterol transport in the body.

The Role of the Liver

The liver acts as a central hub in cholesterol homeostasis. Beyond its role in endogenous synthesis, the liver orchestrates the production and secretion of lipoproteins, modulating the systemic distribution of cholesterol. Additionally, the liver uses feedback mechanisms to adjust its synthesis in response to fluctuations in circulating cholesterol levels.

Feedback Mechanisms

Sophisticated feedback loops govern cholesterol levels, ensuring a delicate equilibrium. Elevated cholesterol prompts the downregulation of endogenous synthesis and a reduction in dietary uptake. Conversely, diminished cholesterol levels trigger up-regulation of synthesis and increased uptake, underscoring the body's dynamic control over cholesterol metabolism. Due to this feedback mechanism, dietary cholesterol usually has little impact on blood cholesterol levels except in hyper-responders.

Saturated Fat

The diet-heart hypothesis, connecting dietary elements to heart disease risk, supports recommendations advocating for reduced saturated fat intake. This hypothesis posits that lowering saturated fats can decrease LDL cholesterol levels, thus potentially lowering the risk of heart disease. Many dietary guidelines are based on this premise, advising the limitation of saturated fat consumption to promote cardiovascular health. 

Statins

Statins are the health practitioners' go-to solution for elevated cholesterol. They primarily operate by inhibiting the activity of HMG-CoA reductase, the key enzyme in cholesterol biosynthesis. This inhibition reduces the liver's production of cholesterol, effectively lowering overall cholesterol levels in the bloodstream. Beyond this, statins exhibit anti-inflammatory properties and contribute to the stabilisation of arterial plaques.

The impact of statins extends beyond cholesterol regulation, affecting other vital molecules via the Mevalonate pathway. These include Coenzyme Q10 (CoQ10), essential for mitochondrial energy production, dolichols for protein glycosylation, and isoprenoids crucial for activating small GTPase proteins. The decrease in CoQ10 levels due to statins may lead to side effects like muscle-related symptoms. Hence, some individuals supplement CoQ10 while on statins to counterbalance these effects.

Summary

There is evidence to suggest the appearance of early sterols in microorganisms roughly 2.7 billion years ago. This is an ancient prelude to the development of cholesterol. Long before humans graced the Earth, this molecule embarked on a journey of synthesis and has intricately woven itself into the fabric of life. Human physiology is a masterpiece of complexity and has strict mechanisms in place to ensure balance in every molecular movement.

Cholesterol, often misunderstood, plays a crucial role in our bodies. It shapes our cells, crafts hormones, and shuttles through our bloodstream on 'boats' called lipoproteins. While our liver creates most of it, the cholesterol we eat might not impact our blood levels as much as we thought. Statins help lower cholesterol, but they also affect other vital molecules. Understanding this complex story reveals the intricate dance of cholesterol in our bodies – a tale still evolving, waiting to be fully understood.