Navigating Metabolic Highways: Lipid Metabolism and Transport in the Human Body

Lipid metabolism constitutes a vital area of human physiology, given that a large number of life-sustaining functions depend on it. The human body, after ages of evolutionary development, has been endowed with intricate pathways for metabolising these energy-dense hydrophobic macromolecules at the cellular level.

But whereas hydrophobicity, the water-repellent nature of lipids, is crucial for their functions, for example, energy storage, it is a challenge to their transport within an aqueous environment, such as in the bloodstream. The answer? lipoproteins, complexes that dynamically transport lipids throughout the body.

It is well recognized that a malfunction in this process of lipid transport, such as high levels of LDL cholesterol, is a major risk for cardiovascular complications. However, it is also important not to forget the physiological effects of lipids, as instantiated by the case of the central nervous system.

Lipoproteins at a Glance

Lipoproteins have a core of triglycerides and cholesterol esters (an inactive, highly hydrophobic form of cholesterol), and on the outside, a phospholipid monolayer. Special proteins, called apolipoproteins, are integrated into this shell for stability. The structure of a typical lipoprotein is shown below for reference.

Source: https://my.clevelandclinic.org/health/articles/23229-lipoprotein

The densities of the 5 lipoprotein classes; chylomicrons, VLDL, IDL, LDL, and HDL; increase in that order, correlating with the fall of their lipid:protein ratio. These also differ in their functions, abundance, and composition.

Chylomicrons are synthesized in enterocytes, shortly after you eat a fat-containing meal, to carry dietary fat and cholesterol absorbed in the intestine to peripheral tissues, i.e. muscle and adipose. Once they reach their site of action, lipoprotein lipase in the inner lining of capillaries catalytically hydrolyses triglycerides into free fatty acids to provide energy. Chylomicrons are prevalent only during post-prandial timeframes, i.e. shortly after a meal.

Very low density lipoproteins (VLDL) are formed in the liver to carry endogenously synthesized triglycerides and cholesterol to peripheral tissues, which again is facilitated by LPL. VLDL is normally always present in small amounts. Fasting, however, causes VLDL to enormously increase, which makes sense, as fasting causes a lack of dietary lipids, thereby necessitating a supplementary supply of lipids from the liver. VLDL increases with carbohydrate intake, so watch out for your carbohydrate intake! High VLDL is tied to cardiovascular diseases, as remnants easily penetrate arterial tissue.

When VLDL releases its supply of free fatty acids, it shrinks, transforming into intermediate density lipoproteins (IDL), which returns to the liver where it is either taken up or further converted by hepatic lipase into LDL particles. Thus, IDL is transitional between VLDL and LDL particles.

Low density lipoproteins (LDL) or ‘bad’ cholesterol, derived from IDL, transport the majority (two-thirds) of circulating cholesterol into peripheral tissues through the process of receptor-mediated endocytosis. For instance, adrenal glands receive the cholesterol needed for steroid synthesis from LDL. The liver clears LDL through the same process at a constant rate to regulate circulating blood cholesterol, unless this process gets disrupted or overwhelmed, leading to LDL buildup in the bloodstream. The chief culprit for this is poor lifestyle habits, i.e. a diet rich in saturated fat, lack of physical activity, obesity, tobacco consumption, and alcohol intake, etc. The accumulation of LDL is known to cause atherosclerosis by invading the tunica intima, the innermost layer of the artery, resulting in inflammation after getting oxidized into oxLDL. Macrophages attempt to remove debris but are converted into foam cells if they get overloaded with oxLDL, increasing plaque formation risk instead.

High density lipoproteins (HDL) play a very crucial role in reverse cholesterol transport. This involves gathering excess cholesterol from peripheral tissues and plaques for reuse or excretion via the liver. It thus acts as a shield against the accumulation of lipids in blood. By scavenging free cholesterol from the blood, HDL keeps the endothelium of blood vessels healthy and combats inflammation. Beyond simply raising HDL levels in the blood, emerging research aims to improve its functionality as well.

And yet, one may ask: what makes lipids critical for human life? The truth is that lipids are central to the smooth functioning of many of our organs. The brain, one of our vital organs, can be taken as a case study to showcase this.

Essential Fatty Acids: DHA and EPA

Docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) are long-chain omega-3 polyunsaturated fatty acids (PUFAs). They are conditionally essential (must be obtained from our diet at times) as our bodies are not very efficient in biosynthesising them. DHA serves structural functions in neuronal membranes and retinal photoreceptors, while EPA is anti-inflammatory as it shifts eicosanoid signalling away from the pro-inflammatory derivatives of omega-6 fats. Omega-3 fatty acids are also tied to cognitive development, healthy brain ageing, and mood stabilisation.

Lipids in the Brain: Function and Transport

The brain is the most lipid-rich organ in the body: lipids account for over 70% of the dry mass of myelin, and are also abundant in grey matter membranes, where they influence membrane fluidity, receptor function, and synaptic signalling. The high-lipid content of myelin is required for rapid nerve conduction and axon health.

Since the blood-brain barrier restricts the passage of many molecules from the blood, cholesterol is primarily synthesised in situ. The brain even possesses a distinct lipidome (lipid composition) relative to plasma. Still, the aforementioned PUFAs have to be obtained externally as they’re non-negotiable for neurodevelopment.

Connecting the Dots: Lipids, Pathology, and Emerging Therapies

This article has built a holistic picture of lipid biology: lipoproteins are the system of lipid transport between different body areas, including the CNS, where lipids play essential roles like maintaining neural circuitry and functioning, etc. As one may expect, with such intricacy, lipid-related dysfunctions can occur in any part of this system, such as in arterial walls with an impaired clearance of LDL particles, in the CNS with an imbalance of omega-3 & omega-6 fatty acids, thus triggering neurodegeneration, etc.

In accordance with this, treatment options have evolved from traditional lipid-lowering therapies with statins or PCSK9 inhibitors, to modifications in diet, such as supplying more omega-3, to highly specialized therapy aimed at different lipoprotein subclasses.

Closing Thoughts

All in all, the metabolism of lipids is an intricate but interconnected network, encompassing our diet, processing by the liver, and utilisation by individual organs like the brain. Appreciating this complexity makes it easier to see the importance of lipids for cardiovascular & neurological wellbeing.

References

1. Chen, C. H., Sawamura, T., et al. (2025, March 5). Evolving concepts of low-density lipoprotein: From structure to function. European Journal of Clinical Investigation. https://www.ovid.com/journals/ejci/pdf/10.1111/eci.70019~evolving-concepts-of-low-density-lipoprotein-from-structure

2. Dighriri, I. M., Alsubaie, A. M., et al. (2022, October 9). Effects of omega-3 polyunsaturated fatty acids on Brain Functions: A systematic review. Cureus. https://www.cureus.com/articles/116591-effects-of-omega-3-polyunsaturated-fatty-acids-on-brain-functions-a-systematic-review#!/

3. Gugliucci, A. (2024, January 18). The Chylomicron Saga: Time to focus on postprandial metabolism. Frontiers. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1322869/full

4. Ma, Z., Zhong, J. et al. (2024, October 28). The functions of apolipoproteins and lipoproteins in health and disease - molecular biomedicine. SpringerLink. https://link.springer.com/article/10.1186/s43556-024-00218-7

Wulff, A. B., & Nordestgaard, B. G. (2023, June 26). Lipids and lipoproteins. Ugeskriftet.dk. https://ugeskriftet.dk/dmj/lipids-and-lipoproteins