Introduction

Fats and lipids are an essential component of the homeostatic function of the human body. Lipids contribute to some of the body’s most vital processes.

Lipids are fatty, waxy, or oily compounds that are soluble in organic solvents and insoluble in polar solvents such as water. Lipids include:

• Fats and oils (triglycerides)
• Phospholipids
• Waxes
• Steroids

Fundamentals

Fats and oils are esters made up of glycerol (a 3-carbon sugar alcohol/polyol) and 3 fatty acids. Fatty acids are hydrocarbon chains of differing lengths with various degrees of saturation that end with carboxylic acid groups. Additionally, fatty acid double bonds can either be cis or trans, creating many different types of fatty acids. Fatty acids in biological systems usually contain an even number of carbon atoms and are typically 14 carbons to 24 carbons long. Triglycerides store energy, provide insulation to cells, and aid in the absorption of fat-soluble vitamins. Fats are normally solid at room temperature, while oils are generally liquid.[1]

Lipids are an essential component of the cell membrane. The structure is typically made of a glycerol backbone, 2 fatty acid tails (hydrophobic), and a phosphate group (hydrophilic). As such, phospholipids are amphipathic. In the cell membrane, phospholipids are arranged in a bilayer manner, providing cell protection and serving as a barrier to certain molecules. The hydrophilic part faces outward and the hydrophobic part faces inward. This arrangement helps monitor which molecules can enter and exit the cell. For example, nonpolar molecules and small polar molecules, such as oxygen and water, can easily diffuse in and out of the cell. Large, polar molecules, for example, glucose, cannot pass freely so they need the help of transport proteins.

Another type of lipid is wax. Waxes are esters made of long-chain alcohol and a fatty acid. They provide protection, especially to plants in which wax covers the leaves of plants. In humans, cerumen, also known as earwax, helps protect the skin of the ear canal.

A further class includes steroids, which have a structure of 4 fused rings. One important type of steroid is cholesterol. Cholesterol is produced in the liver and is the forerunner to many other steroid hormones, such as estrogen, testosterone, and cortisol. It is also a part of cell membranes, inserting itself into the bilayer and influencing the membrane’s fluidity.[2]

Mechanism

The interaction between water-fearing and fat-loving displays more clearly during lipid transport in plasma. Both cholesterol and triglycerides are nonpolar lipid molecules. Therefore, they must travel in the polar plasma with the help of lipoprotein particles. The main goal of lipoprotein is to help transport lipids (hydrophobic) in water. The structure of lipoprotein consists of triglycerides, cholesterol, phospholipids, and apolipoproteins. Apolipoproteins mainly function as carrier proteins but also serve as cofactors for enzymes that metabolize lipoproteins and help in lipid component exchange among lipoproteins. Some examples of lipoproteins include chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Each one is used in a different phase of lipid transport.[3]

Chylomicrons are large triglyceride-rich particle made in the endoplasmic reticulum of enterocytes of the small intestine. They play a role in carrying dietary triglycerides and cholesterol to peripheral tissues and the liver.[4] Apo B-48 is an apolipoprotein that is involved in chylomicron assembly, thus having a vital role in the absorption of dietary fats and fat-soluble vitamins.[5]

VLDLs are triglyceride-rich particles made in the liver.[4] Apo B-100 is important for VLDL production.[5]

IDL particles, which are cholesterol-rich, are created when triglycerides are removed from VLDL by muscle and adipose tissue.[4]

LDL particles are formed from VLDL and IDL particles and are also rich in cholesterol. LDL transports most of the cholesterol in the blood and is colloquially considered “bad cholesterol.”[4] Apo B-100 plays a key role by acting as a ligand for the LDL receptor-mediated uptake of LDL particles by the liver and other tissues.[5]

HDL particles are cholesterol and phospholipid-rich, and aid in reverse cholesterol transport from peripheral tissues to the liver, where it is removed. As such, HDL cholesterol is considered “good cholesterol”.[4]

To expand, the transport of plasma lipids involves two routes. One is an exogenous path for the transport of dietary triglycerides and cholesterol from the small intestine.[3] In the small intestine, triglycerides are broken down with the help of enzymes and bile acids, such as cholic acid. First, the early digestive products, such as free fatty acids, trigger release of the hormone Cholecystokinin (CCK) by the duodenum. CCK activity stimulates emptying of the gallbladder, which leads to bile release into the small intestine, and further triggers the pancreas to release pancreatic digestive enzymes into the intestine.[6] The detergent action of bile acids helps to emulsify fats, which allows easier hydrolysis by water-soluble digestive enzymes due to the increased surface area. One important enzyme, pancreatic lipase, breaks down triglycerides to produce free fatty acids and monoacylglycerol, which are absorbed by the intestinal mucosal cells with the help of mixed micelles that were created in the process.[7]

Fatty acids are made of 12 carbons or less and are absorbed through the intestinal mucosal villi. They enter the bloodstream through capillaries, reach the portal vein, and are taken to the liver with the help of lipid carrier proteins to be used for energy. However, longer-chain fatty acids are absorbed by the intestinal mucosa from the lumen, where they are re-esterified to form triglycerides and are incorporated into chylomicrons; the chylomicrons are then released into intestinal lymph, secreted into blood circulation through the thoracic duct, and attach to capillary walls in adipose and skeletal muscle tissue. At the attachment points, chylomicrons interact with the enzyme lipoprotein lipase, leading to triglyceride core breakdown and free fatty acid release. The fatty acids penetrate through the capillary endothelial cells and are either stored in adipose cells or oxidized in skeletal muscle cells. From the triglyceride core hydrolysis, remnants are removed from the plasma and brought to hepatic cells to be broken down by lysosomes. This causes the release of cholesterol, which can be turned into bile acids, integrated into VLDL, or even combined in bile.

The other pathway is via the endogenous system, in which cholesterol and triglycerides travel from the liver and other non-intestinal tissues into circulation. The liver produces triglycerides from carbohydrates and free fatty acids. These triglycerides are then released into plasma in the core of VLDL. The VLDL particles interact with lipoprotein lipase in tissue capillaries, causing triglyceride core hydrolysis and free fatty acid liberation. Some of the remnant particles are taken out of plasma and bind to hepatic cells. The rest of the remnant particles, however, transform into LDL particles, which then provide cholesterol to cells that have LDL receptors, such as the gonads, adrenal glands, skeletal muscle, lymphocytes, and kidneys.

In addition to the functions mentioned above, when energy is needed, fat can also be broken down for energy. Glucagon (released during fasting) or epinephrine (released during exercise) activates adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) for fatty acid liberation. These fatty acids can then be used for energy by most tissues with the help of mitochondria and the Krebs cycle.[3]

Testing

Tests can be performed to determine the levels of the different types of lipids in the blood. While cholesterol levels are usually steady, triglyceride levels vary from day to day and rise after meals. Therefore, a blood sample called a “lipid panel" taken for lipid testing should occur after a 12-hour fasting period, which allows the clearance of chylomicrons from the blood. For more accurate results, patients should not take any medications that could change blood lipid levels or take the test during times of stress or illness.[3]

Clinical Significance

Abnormal levels of cholesterol and triglycerides in the blood are often due to the unusual assembly, breakdown, or transport of their lipoprotein particles. An increased level of plasma lipoproteins is termed hyperlipoproteinemia, while the decreased level of plasma lipoproteins is termed hypolipoproteinemia.

Levels of plasma lipids are good indicators of the risk of cardiovascular disease (CVD). For instance, hyperlipoproteinemia is related to a greater risk of atherosclerotic cardiovascular disease, as well as a higher occurrence of ischemic vascular disease and development of fatty deposits under the skin, known as xanthomas and xanthelasmas. Elevated plasma concentrations of total cholesterol and LDL are linked with an increased risk of coronary heart disease and raised plasma triglycerides.  An increase in VLDL is related to a greater prevalence of atherosclerotic heart disease. However, elevated levels of HDL cholesterol may protect against atherosclerotic heart disease, due to its ability to prevent excessive accumulation of cholesterol in the body. There are several types and subtypes of lipid-related disorders and they are described below.

Hypertriglyceridemia is a disorder with high levels of triglycerides in the blood. Five main disorders result in hypertriglyceridemia:

• Familial hypertriglyceridemia: An autosomal dominant disorder that results in elevated VLDL levels in plasma
• Familial combined hyperlipidemia: An autosomal dominant disorder, characterized by the excessive synthesis of lipoproteins containing apolipoprotein B
• Congenital lipoprotein lipase deficiency: An autosomal recessive disorder, which results in low to no lipoprotein lipase activity; typically, chylomicrons build up in the blood and eruptive xanthomas develop   
• Apoprotein CII deficiency: An autosomal recessive disorder, characterized by the lack of apoprotein CII, an essential cofactor for lipoprotein lipase activity; there is usually chylomicron and VLDL accumulation in the plasma
• Familial dysbetalipoproteinemia: A disorder in which there is a defect in apolipoprotein E; due to the buildup of remnant VLDL particles in the blood, there are higher plasma levels of cholesterol and triglyceride

Hypercholesterolemia is a disorder in which there are high cholesterol levels in the blood. Three main conditions result in hypercholesterolemia:

• Polygenic hypercholesterolemia: The most common disorder to raise cholesterol levels; there are many genes involved that elevate LDL concentration in plasma
• Familial hypercholesterolemia: An autosomal dominant disorder in which the gene for the LDL receptor is defective, so removal of LDL from plasma is less than effective
• Familial combined hyperlipidemia: Discussed previously above

Hyperalphalipoproteinemia is a disorder with elevated HDL levels in the plasma. Most cases are inherited through a dominant or polygenic manner and are linked to a lower risk of coronary artery disease.[8]

High levels of plasma lipids can also be due to dietary factors, such as ingesting excess calories, saturated fatty acids, and cholesterol, as well as from medication use.

Hypolipoproteinemia refers to relatively low levels of lipids in the blood. Such a condition may be associated with a genetic component or perhaps other conditions like anemia or an overactive thyroid.

Hypolipoproteinemias include three primary conditions:

• Hypoalphalipoproteinemia: A reduction in HDL cholesterol levels in plasma that is associated with a greater risk of coronary heart disease
• Abetalipoproteinemia: An autosomal recessive disease; it is caused by apoprotein B deficiency and is characterized by the lack of chylomicrons, LDL, and VLDL in the blood
• Tangier disease: An autosomal recessive disorder classified by an absence of plasma HDL, which results in the synthesis of abnormal chylomicron remnant

Other disorders in which abnormal structural lipoproteins and their concentrations are present in the blood are referred to as dyslipoproteinemia. One disorder of this kind is LCAT (lecithin-cholesterol acyltransferase) deficiency. Low activity of this enzyme causes unesterified cholesterol to accumulate in plasma and tissues.[3]

Further diseases include lipid storage diseases, or lipidoses, which are genetic diseases in which atypical amounts of lipids accumulate in cells and tissues. Lipidoses are characterized by the absence of enzymes needed to metabolize lipids or a defect in the proper functioning of enzymes. This abnormal fat deposition can lead to severe damage in cells and tissues, including the brain, heart, liver, kidney, and spleen. Two examples of lipidoses include Gaucher disease and Tay-Sachs disease. Gaucher disease is caused by a deficiency in the enzyme glucocerebrosidase, resulting in hepatosplenomegaly, pancytopenia, and bone crises. Tay-Sachs is caused by the absence of the enzyme hexosaminidase-A and leads to a progressive loss of mental and physical capabilities.[9]

While treatment for lipidoses is unspecific and mainly limited to enzyme replacement therapy, there are medication options that help lower lipid plasma levels. However, it is of the utmost importance to manage dietary consumption and lifestyle changes either before or in conjunction with starting medication. Some of these changes may include a reduced-calorie diet, exercise, and quitting smoking if one is a smoker. Popular medication options include statins, fibrates, omega-3 fatty acids, bile acid sequestrants, a cholesterol-absorption inhibitor, and nicotinic acid. Of these choices, statins are the most widely prescribed treatment.[10] They can lower cholesterol biosynthesis, primarily in the liver by competitively inhibiting HMG-CoA reductase, the rate-limiting enzyme for cholesterol production. Statins also aid in the uptake and destruction of LDL. They have contributed to the progress made in the primary and secondary prevention of coronary heart disease, and have lowered death rates in coronary patients.[11]