Cholesterol: Definition, Structure, Synthesis, Types and Functions

Cholesterol is a lipid found in the cell membranes of all animals. It is an important component of the cell membrane and plays a vital role in maintaining the structural integrity and fluidity of the membrane. This article discusses the definition, structure, synthesis, and classification of cholesterol and its derivatives, and provides a brief overview of their physiological functions and industrial applications.

What Is Cholesterol?

Cholesterol is a derivative of cyclopentane polyhydrophenanthrene. The chemical formula is C₂₇H₄₆O, which is white or light yellow crystal. Its solubility is similar to fat, insoluble in water, and easily soluble in solvents such as ether and chloroform. Cholesterol was discovered in gallstones as early as the 18th century. In 1816, chemist Benshall named this lipid-like substance cholesterol. Cholesterol is widely present in animals, especially in the brain and nervous tissue. It is also found in kidneys, spleen, skin, liver and bile. It is an indispensable and important substance for animal tissue cells. The synthesis of this molecule occurs in part in a membrane world, where the enzymes, substrates, and products involved are often extremely hydrophobic.

Cholesterol Definition

Cholesterol is considered a lipid-type molecule. Generally, lipid substances are mainly divided into two categories: fats and lipoids. Fat (mainly triglycerides) is the most abundant lipid in the human body and is a major source of energy in the body. Lipoids are the basic components of biological membranes, accounting for about 5% of body weight, including phospholipids, glycolipids and cholesterol. Therefore, cholesterol not only participates in the formation of cell membranes, but is also a raw material for the synthesis of bile acids, vitamin D and steroid hormones. In addition, cholesterol can be converted into bile acids, steroid hormones, and 7-dehydrocholesterol through metabolism, and 7-dehydrocholesterol will be converted into vitamin D3 by ultraviolet irradiation, so cholesterol is not a harmful substance to the human body.

Cholesterol Structure

From a chemical perspective, cholesterol is a rigid and almost planar molecule with a steroidal backbone consisting of four fused rings, three six-membered rings, and one five-membered ring, usually in alphabetical order from A to D (1, 2-cyclopentylperhydrophenanthrene ring system) (Figure 1A). Therefore, the cholesterol molecule contains four basic domains (Figure 1B). In domain I, the polarity of the 3-hydroxyl group constitutes the active site for hydrogen bonding interactions with a variety of biomolecules, such as phospholipids in membranes. In domain II, the absence of methyl groups at C-4 and C-14 directly affects the planarity of the molecule, while in domain III, the native (R) configuration at C-20 determines the "right-hand" side chain "Conformation. Finally, in domain IV, the conformation and length of the side chains are closely related to intermolecular contacts. The presence of the hydrophilic 3-hydroxyl head group on the A-ring, together with the hydrophobic hydrocarbon body, confer amphiphilicity to the molecule, making cholesterol the most recognized sterol.

Fig. 1. Structure of cholesterol. (A) Numbering and ring labeling convention for cholesterol; (B) Four domains of cholesterol (Molecules. 2018, 24(1): 116).

Cholesterol in Membrane

Cholesterol plays a vital role in life, especially in cell membranes, and is a precursor for the biosynthesis of several steroid hormones. Cholesterol makes up 30-50% of cell membrane lipids (1 in every 2-3 lipids) in all cells of the body. In cell membranes, which are essentially bilayers of phospholipids, cholesterol exerts a strong influence on the fluidity, microdomain structure (lipid rafts), and permeability of the membrane by interacting with the hydrophilic headgroups and hydrophobic tails of phospholipids. Furthermore, changes in the stereochemistry and oxidation state of the fused rings, side chains, and cholesterol functional groups yield a variety of biologically important molecules, such as bile acids, vitamin D, and several steroid hormones. Interestingly, 13 Nobel Prizes have been awarded to scientists who studied the structure of cholesterol, its biosynthetic pathways and metabolic regulation. Unfortunately, cholesterol gets a bad rap as it is increasingly linked to a variety of cardiovascular and neurodegenerative diseases, among others.

Cholesterol Synthesis

For many years, cholesterol has become an attractive starting material or model system for organic synthesis due to its easily derivatized functional groups, availability, and low cost. Many useful chemical and enzymatic reactions are now widely used in multistep steroid conversions, producing products of practical interest. Chemical transformations range from simple, such as manipulation of functional groups, to more complex, such as C-H activation or C-C bond formation with organometallic reagents. At present, the chemical synthesis of cholesterol focuses on cholesterol oxidation reaction, substitution of 3β-hydroxyl group, addition of C5=C6 double bond, C-H functionalization, and C-C bonding reaction. In addition, simple derivatization reactions of cholesterol are also widely used, such as the preparation of carboxylic and inorganic acid esters, aliphatic and aromatic ethers, simple acetals or glycosides.

Cholesterol Types

Cholesterol derivatives are compounds derived from cholesterol through various chemical modifications. These derivatives can be divided into several chemical classes based on their structure and function.

Oxysterol

Oxysterols are oxidized derivatives of cholesterol formed by enzymatic or non-enzymatic oxidation reactions. These compounds play important roles in regulating cholesterol metabolism, inflammation, and cell signaling. Some well-known oxysterols include 7-ketocholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol. Oxysterols have been implicated in the pathogenesis of several diseases, including atherosclerosis, neurodegenerative diseases, and cancer.

Bile Acid

Bile acids are steroid molecules synthesized from cholesterol in the liver and secreted into bile to aid in the digestion and absorption of dietary fats. Bile acids are amphiphilic molecules that solubilize dietary lipids and facilitate their transport across the intestinal epithelium. Primary bile acids, such as cholic acid and chenodeoxycholic acid, are synthesized in the liver, while secondary bile acids, such as deoxycholic acid and lithocholic acid, are produced by intestinal microorganisms through the debinding and dehydroxylation of primary bile acids.

Steroids

Steroid hormones are signaling molecules that regulate a variety of physiological processes, including metabolism, growth, reproduction, and immune responses. These hormones are synthesized from cholesterol in the adrenal glands, gonads, and placenta through a series of enzymatic reactions. Examples of steroid hormones derived from cholesterol include cortisol, aldosterone, testosterone, estrogen, and progesterone. These hormones work by binding to specific receptors in target cells and regulating gene expression and cell signaling pathways.

Vitamins

Vitamin D is a fat-soluble vitamin that is essential for maintaining calcium and phosphate homeostasis, bone health, and immune function. Vitamin D is synthesized from 7-dehydrocholesterol (a precursor of cholesterol) after skin exposure to ultraviolet radiation. The inactive form of vitamin D (called cholecalciferol or vitamin D3) undergoes hydroxylation in the liver and kidneys to form the active hormone calcitriol. Calcitriol regulates calcium absorption, bone mineralization, and immune responses in the intestine by binding to vitamin D receptors in target tissues.

Cholesterol Function

Physiological Functions of Cholesterol

Cholesterol derivatives include a variety of compounds that play crucial roles in various physiological processes in the body. Cholesterol in nature mainly exists in animal foods, and cholesterol is found in a few plants. Most plants contain substances that are structurally very similar to cholesterol, namely phytosterols. Plant sterols (particularly sitosterol) can competitively inhibit cholesterol absorption.

• Form Cholic Acid

Bile is produced in the liver and stored in the gallbladder, where it is released into the small intestine to mix with digested fats. The function of bile is to break large particles of fat into small particles so that they can easily interact with enzymes in the small intestine. In the tail of the small intestine, 85% to 95% of the bile is reabsorbed into the blood, the liver reabsorbs bile acid and circulates it continuously, and the remaining bile (5% to 15%) is excreted with the feces. The liver needs to produce new bile acid to make up for this 5% to 15% loss, and cholesterol is needed at this time.

• Make Up Cell Membrane

Cholesterol is an important component of the cell membrane, which surrounds every cell in the human body. Cholesterol is its basic component, accounting for more than 20% of plasma membrane lipids. Some people have found that feeding animals a diet lacking in cholesterol increases the fragility of the animals' red blood cells, which can easily cause cell rupture. Studies have shown that when the temperature is high, cholesterol can prevent the disordering of the bilayer; when the temperature is low, it can interfere with its ordering, prevent the formation of liquid crystals, and maintain its fluidity. Therefore, it is conceivable that without cholesterol, cells cannot maintain normal physiological functions and life will terminate.

• Synthetic Hormones

Hormones are chemical messengers that coordinate the metabolic actions of different cells in a multicellular organism. They participate in the metabolism of various substances in the body, including the metabolism of sugar, protein, fat, water, electrolytes and minerals, etc., and are very important for maintaining normal physiological functions of the human body. Various hormones released by the human body's adrenal cortex and gonads, such as cortisol, aldosterone, testosterone, estradiol, and vitamin D, are all steroid hormones, and their precursor is cholesterol.

Industrial Applications of Cholesterol

In recent years, cholesterol compounds have found widespread use in diverse research fields such as drug delivery, bioactivity, liquid crystals, gelling agents, bioimaging, and purely synthetic applications. Numerous examples of cholesterol derivatives are of interest for their use in preclinical and clinical liposomal drug formulations to reduce membrane fluidity and provide favorable drug retention properties. Furthermore, in the past few years, some new cholesterol derivatives have also been developed for pharmacological applications such as anticancer, antibacterial, or antioxidants.

• Cholesterol for Drug Delivery

Drug delivery is a method or process of administering pharmaceutical compounds to achieve a therapeutic effect in humans or animals. Drug delivery systems can in principle provide enhanced efficacy, reduced toxicity, or both for various types of drugs. Cholesterol derivatives have been widely explored as drug delivery vehicles due to their biocompatibility, low toxicity, and ability to self-assemble into various nanostructures. These derivatives can be chemically modified to be incorporated into drug molecules, enabling targeted delivery and controlled release of therapeutics. For example, cholesterol-modified liposomes have been used to deliver anticancer drugs to tumor cells, improving drug efficacy and reducing off-target effects. Furthermore, cholesterol-based micelles and nanoparticles have shown promise in delivering poorly water-soluble drugs, improving their bioavailability and therapeutic efficacy.

• Cholesterol with Biological Activity

In the search for new anticancer agents, antibacterial agents, or antioxidants with improved efficacy, many novel cholesterol derivatives with various bioactive scaffolds have been developed. For example, cholesterol analogs such as 25-hydroxycholesterol have shown anticancer activity by inducing apoptosis in cancer cells and inhibiting tumor growth. Likewise, cholesterol derivatives exhibit antimicrobial properties against various pathogens, making them potential candidates for the development of novel antimicrobial agents. Additionally, cholesterol derivatives with antioxidant properties have been studied for their ability to scavenge free radicals and protect cells from oxidative damage, which may provide therapeutic benefits in the treatment of oxidative stress-related diseases.

• Cholesterol-Based Liquid Crystals

Alcohol-based liquid crystals, multipurpose materials with distinctive optical, electrical, and mechanical properties, have been created using cholesterol derivatives. These liquid crystals are ideal for a range of applications, such as medication delivery systems, displays, and sensors, since they can self-organize into ordered structures. The phase behavior and characteristics of alcohol-based liquid crystals can be altered by cholesterol derivatives acting as surfactants or stabilizers. Through the manipulation of cholesterol derivatives' chemical structure, scientists can manipulate the characteristics and shape of alcohol-based liquid crystals to tailor them for certain uses.

• Cholesterol-Based Gelators

Small organic molecules known as low molecular weight organogelators self-assemble in organic solvents or water to create a three-dimensional network that retains the liquid phase and creates a gel. Due to the wide range of possibilities this class of chemicals has, including tissue engineering and alternative biomaterials for drug administration, they have garnered a lot of attention recently. In order to create new generations of steroid low-molecular-mass gelators, different building blocks are frequently assembled around the steroid units that can be positioned via linkers, including steroid derivatives, linker units, and aromatic platforms. In order to make topical creams, ointments, and gels for drug administration and skin care applications, cholesterol-based gelling agents have been utilized. Moreover, the behavior of these gelling agents can be altered to be pH-responsive or thermoresponsive, enabling the regulated release of active substances.

• Cholesterol for Bioimaging

In order to see biological structures and processes, cholesterol derivatives have been employed in biological imaging as fluorescent probes or contrast agents. Imaging molecules or nanoparticles combined with cholesterol derivatives allow researchers to image particular tissues or cells. For instance, cholesterol-modified nanoparticles have been applied to in vivo cancer cell imaging and targeted medication administration. Fluorescent cholesterol derivatives can also be used to detect biological processes in real time or mark biomolecules, offering important new information about drug interactions and disease mechanisms.

• Cholesterol for Chemical Synthesis

Cholesterol derivatives are synthesized through various chemical reactions and modifications to adapt their properties to specific applications. These derivatives can be functionalized with different groups or substituents to impart desired properties such as solubility, stability or biological activity. For example, cholesterol derivatives with hydrophilic groups have been synthesized to improve their water solubility and bioavailability for drug delivery applications. Likewise, cholesterol derivatives with reactive functional groups can be used as building blocks for the synthesis of new materials or bioactive compounds with enhanced properties.

Cholesterol Molecule

BOC Sciences is a leading supplier of lipid and cholesterol derivatives for research and development purposes. We offer a variety of cholesterol products, including cholesterol standards, cholesterol derivatives, and cholesterol synthesis intermediates. Our cholesterol products are highly purified and characterized to ensure their quality and consistency. Our experienced team of chemists can design and synthesize cholesterol derivatives, including synthesis of cholesterol derivatives with specific modifications or labels, for a variety of applications such as drug discovery, lipid metabolism studies, and biomarker development.

Reference

1. Albuquerque, H.M.T. et al. Cholesterol-Based Compounds: Recent Advances in Synthesis and Applications. Molecules. 2018, 24(1): 116.