Biochemistry, Lipids

Article Author:
Saba Ahmed
Article Editor:
Owais Ahmed
Updated:
10/27/2018 12:31:41 PM
PubMed Link:
Biochemistry, Lipids

Introduction

People today are taught to be “hydrophobic.” Fats are said to be bad for people, and they should not be included in the diet. However, fats and lipids are an essential part of the everyday functioning of the human body, down to the molecular level. They are used for some very important processes described below.

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

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

They are a significant part of biological membranes as well as of the myelin sheath that coats and protects the nerves for our neurological functioning.

Fundamentals

Fats and oils are esters made up of glycerol, which is a 3-carbon sugar, and 3 fatty acids. Fatty acids are hydrocarbon chains of differing lengths with various degrees of unsaturation that end with carboxylic acid groups. Additionally, fatty acid double bonds could either be cis or trans, which creates 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, as well as aid in the absorption of fat-soluble vitamins. Fats are normally solid at room temperature, while oils are generally liquid.[1]

An important biological function of lipids involves phospholipids, which comprises the cell membranes of all our cells. They are typically made of a glycerol backbone, 2 fatty acids, and a phosphate group. Phospholipids are amphipathic since they have both hydrophobic and hydrophilic properties. The fatty acid “tail region” is hydrophobic, while the phosphate-containing “head group” is hydrophilic. In the cell membrane, phospholipids arrange in a bilayer manner, providing the cell protection and serving as a barrier to certain molecules. Meaning that the water-loving part faces outwards and the fat-loving part faces inwards. This arrangement helps bring important molecules in and out of the cell. For instance, nonpolar molecules and small polar molecules, like oxygen and water, can easily diffuse, but large, polar molecules, for example, glucose, cannot pass. The large polar molecules, therefore, pass through the membrane with the help of transport proteins.

Another component of lipids are waxes; waxes are esters made of an alcohol and fatty acid. They provide protection, especially to plants in which wax covers the leaves of plants.

A further class includes steroids, which are made up 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, where it inserts into the bilayer and influences the membrane’s fluidity; cholesterol is even found in the bloodstream.[2]

Mechanism

A clinical example of water-fearing and fat-loving scenarios happens during lipid transport in the plasma. Both cholesterol and triglycerides, since they are nonpolar lipid molecules, must travel in the polar plasma with the help of lipoprotein particles. Lipoproteins are globular particles that consist 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 particles that are triglyceride-rich and produced in the intestine. They play a role in carrying dietary triglycerides and cholesterol to peripheral tissues and the liver.[4] Apo B-48 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 by 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 cholesterol-rich. LDL transports most of the cholesterol in the blood and is considered “bad cholesterol.”[4] Apo B-100 has a key role, in which it acts 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. Therefore, HDL cholesterol is considered “good cholesterol”.[4]

Going into further detail, the transport of plasma lipids involves 2 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. Firstly, the early digestive products, such as free fatty acids, trigger release of the hormone CCK by the duodenum. CCK activity stimulates emptying of the gallbladder, which leads to bile release into the intestine, and causes 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]

Microscopically, fatty acids made of 12 carbons or less 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 have interactions 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 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.

On top of all of that, 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]

Clinical Significance

Abnormal levels of cholesterol and triglycerides in the blood usually occur due to the unusual assembly, breakdown, and transport of their lipoprotein particles. Increased plasma lipoproteins are termed as hyperlipoproteinemia, while decreased plasma lipoproteins are termed as 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, known as xanthomas and xanthelasmas. Elevated plasma concentration of total cholesterol and LDL are linked with an increased risk of coronary heart disease and raised plasma triglycerides, and VLDL are related to a greater prevalence of atherosclerotic heart disease. However, elevated levels of HDL cholesterol may protect against atherosclerotic heart disease, due to HDLs function of preventing excessive accumulation of cholesterol in the body.

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

  • Familial hypertriglyceridemia: Has autosomal dominant inheritance that causes elevated VLDL levels in plasma 
  • Familial combined hyperlipidemia: An autosomal dominant disorder, characterized by excessive synthesis of lipoproteins containing apolipoprotein B 
  • Congenital lipoprotein lipase deficiency: Has autosomal recessive inheritance, which causes low to no lipoprotein lipase activity; typically there is chylomicron buildup in the blood and development of eruptive xanthomas   
  • Apoprotein CII deficiency: Has autosomal recessive inheritance, 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 triglycerides

Hypercholesterolemia is a disorder in which there are high cholesterol levels in the blood. There are 3 main conditions causing hypercholesterolemia:

  • Polygenic hypercholesterolemia: Tthe 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 not as 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 with a lower risk of coronary artery disease.

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 drug intake.

Hyperlipoproteinemias include three primary conditions:

  • Hypoalphalipoproteinemia: Characterized by decreased HDL cholesterol levels in plasma and 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: Has autosomal recessive inheritance; plasma HDL is absent, which results in the synthesis of abnormal chylomicron remnants

Other disorders in which abnormal structural lipoproteins and their concentrations are present in 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, such as in 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, while Tay-Sachs is caused by the absence of the enzyme hexosaminidase-A and leads to a progressive loss of mental and physical capabilities.[8]

While treatment for lipidoses is unspecific and mainly limited to enzyme replacement therapy and pain management, there are medication options to lower lipid plasma levels; these include statins, fibrates, omega-3 fatty acids, bile acid sequestrants, a cholesterol-absorption inhibitor, and nicotinic acid. However, statins are the most widely prescribed treatment.[9] They can lower cholesterol biosynthesis, primarily in the liver, due to being a competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme for cholesterol production. Statins also aid in the uptake and destruction of LDL. They have made progress in the primary and secondary prevention of coronary heart disease, and have lowered death rates in coronary patients.[10]

Tests can also 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. Additionally, patients should not take any medications that could change blood lipid levels or take the test during times of stress/illness for more accurate results.[3]