Hyperlipidemia is defined as an increase in the concentration of lipids in the blood. The term “lipids” is the scientific name for fats. Since what is actually increased are the molecules that bind lipids and proteins (lipoproteins), some authors prefer to use the term “hyperlipoproteinemia”.
The terms “hyperlipidemia”, “hyperlipemia” and “hyperlipoproteinemia” have long been used in clinical practice. However, some authors prefer to speak of “dyslipidemia”, “dyslipemia” or “dyslipoproteinemia”. These terms better reflect disorders of lipid and lipoprotein metabolism and transport.
Furthermore, they encompass not only elevated lipids (hyperlipidemia), but also disorders that are frequently encountered in clinical practice. For example, decreased high-density lipoprotein (HDL) cholesterol and elevated triglycerides. In these cases, the serum cholesterol concentration may be normal.
High blood lipid levels are one of the most important risk factors for atherosclerosis in general and ischemic heart disease in particular. Atheromatous plaques capture cholesterol from low-density lipoprotein (LDL). This initiates and maintains an inflammatory reaction in the artery wall that can lead to blockage.
In most cases, hyperlipidemia does not cause symptoms by itself. Therefore, serum lipid determination is required for its diagnosis. In rare cases, hyperlipidemia directly causes clinical signs or symptoms. Hyperlipidemia is one of the major risk factors for atherosclerosis and coronary artery disease. Its appropriate treatment reduces cardiovascular and total mortality rates. Therefore, all actions taken against hyperlipidemia are of great importance for cardiovascular prevention.
Lipids
Cholesterol is an essential component of mammalian cell membranes and is used to form steroids and bile acids. It is therefore a necessary and fundamental substance for the proper functioning of the body. Many cellular functions depend on membrane cholesterol. Most of the cholesterol contained in plasma circulates in the form of cholesterol esters in the core of lipoprotein particles.
Triglycerides consist of a glycerol with three carbon atoms attached to three fatty acid chains. Triglyceride molecules are transported in the core of lipoproteins. The breakdown of the triglyceride molecule releases fatty acids, which are used as a source of energy.
Lipoproteins are complex structures composed of a phospholipid and free cholesterol shell, a core of cholesterol esters and triglycerides, and protein components called apolipoproteins. They are classified according to their density in plasma. Those rich in triglycerides are chylomicrons and very low-density lipoproteins (VLDL). Those rich in cholesterol are LDL (low-density lipoproteins) and HDL (high-density lipoproteins). Basically, LDL are the lipoproteins that carry cholesterol to the tissues, while HDL are those that collect it and remove it from the tissues.
Macrophages have receptors on their cell membrane that bind to modified lipoproteins (especially oxidized ones). This makes macrophages the cells responsible for removing lipoproteins. These bind to their receptor and are introduced into the cytoplasm of the cell. When the macrophage captures non-oxidized LDL, there is a decrease in the expression of the receptor. Therefore, it stops capturing LDL, leading to their elimination without pathological consequences.
However, when the macrophage takes up oxidized LDL, the receptor activity is not suppressed, allowing the macrophages in the arterial wall to accumulate abundant cholesterol. They then become foam cells and form part of the atheroma plaques. To reach the lipid-laden macrophages, the HDL molecules must cross the endothelial cells in the arterial wall.
Lipid metabolism
The human body needs fats to live. It obtains fats from food, mainly essential fatty acids that it cannot manufacture. Under normal conditions, fat constitutes between 20% and 40% of daily calories. Triglycerides are the most abundant part of ingested fats, and the intestine has mechanisms adapted to their absorption.
When triglycerides reach the intestine in food, their molecules are broken down by lipases in pancreatic juice and dissolved by bile acids. This forms particles known as “intestinal micelles”. These are taken up by the cells of the intestinal wall. Within these cells, fatty acids bind to glycerol to form triglycerides. These, in turn, bind to constitute so-called “chylomicrons”, which quickly pass into the plasma after meals.
In the endothelial cells of the capillaries of adipose tissue (fatty tissue in the body) and muscle cells there is an enzyme called “lipoprotein lipase”. This is what breaks down triglycerides and releases three molecules of fatty acids for each molecule of glycerol. Muscle cells take up fatty acids quickly, since they serve as a source of energy, necessary for muscle contraction. Adipose cells store triglycerides as a reserve to obtain energy if needed. Another part of the fatty acids bind to transport proteins and reach the liver, where they are packaged to form VLDL.
Since food was not always available when humans first appeared on Earth and evolved, the body developed a system to ensure triglyceride availability. In this way, energy demands were met when needed. The liver releases VLDL particles, which are triglyceride-rich lipoproteins that are smaller than chylomicrons. VLDL are broken down by lipoprotein lipase, thus releasing fatty acids. VLDL also exchange triglycerides for cholesterol esters from HDL.
This bidirectional transport of constituents between lipoproteins has several functions. One of them is the transfer of cholesterol from HDL to VLDL residues, so that it can be metabolized in the liver. These exchanges are important in the reverse cholesterol transport process. After VLDL lose triglycerides, their residues remain, constituting molecules with a higher proportion of cholesterol. These undergo changes in their proteins, giving rise to a remnant lipoprotein called “intermediate density lipoprotein” (IDL), which is taken up by the liver.
Low-density lipoproteins
LDL molecules in humans and primates are the main carriers of cholesterol. Cells can obtain the cholesterol they need by synthesizing it from acetate, although this requires many reactions. They also take up cholesterol esters from LDL particles. Within the cell, cholesterol is separated from LDL proteins and used to form part of the cell membrane and/or, where appropriate, to synthesize steroids or fatty acids.
The entire process is carried out by means of a mechanism involving a series of cell proteins that regulate the entry, metabolism, and exit of cholesterol. If enough cholesterol enters the cell, this mechanism acts to reduce the entry and local formation of cholesterol. The cell also increases the amount stored in the form of cholesterol esters and promotes the elimination of cholesterol by increasing its movement towards the cell membrane for its exit.
High-density lipoproteinase
HDL molecules undergo a complicated and poorly understood metabolic process. Approximately 80% of HDL originates in the liver and the remaining 20% in the intestine. HDL particles contain a protein called “apo AI”, phospholipids and, initially, little cholesterol. When these particles contact the cell membrane, they capture the cholesterol associated with the membrane and promote its exit from the cell, binding to the HDL molecule. The exit of cholesterol from macrophages contributes to the reduction of cholesterol in atheromas. HDL also provides cholesterol to tissues that produce steroid hormones and bile acids.
The so-called “reverse cholesterol transport” involves the uptake of cellular cholesterol from extrahepatic tissues, such as lipid-laden macrophages, by HDL particles and their uptake by hepatic receptors. From here, cholesterol is transferred to triglyceride-rich lipoproteins and LDL particles. HDL therefore act as cholesterol carriers from tissues to the liver.
Treatment of hyperlipidemia
The biggest drawback of hyperlipidemia is usually the increased risk of cardiovascular disease. This causes patients to suffer heart attacks, strokes, and other vascular complications. Therefore, therapeutic measures are very important, since they allow this risk to be reduced. In many cases, environmental factors, such as changes in lifestyle (diet, sedentary lifestyle and abdominal obesity), have a significant influence on hyperlipidemia.
Therefore, the treatment of dyslipidemias is based on significant lifestyle changes, such as reducing dietary fats, especially saturated fats, and physical exercise, which improve cardiovascular prognosis. It is also recommended to stop drinking alcohol, especially in cases of hypertriglyceridemia. Patients with hyperchylomicronemia should consume short-chain fatty acids (which are not incorporated into chylomicrons).
It is necessary to monitor other pathologies that may influence plasma lipid concentrations, such as diabetes, obesity, and hypothyroidism. It is also necessary to assess whether the patient is receiving medication that causes hyperlipidemia, in order to see if it is possible to discontinue it.
Finally, the decision to treat hyperlipidemia with drugs depends on the overall cardiovascular risk. In this regard, statins are the drugs of choice for hypercholesterolemia. If this is not sufficient, ezetimibe or bempedoic acid can be added. In high-risk cases, it may be necessary to use specific antibodies or interfering RNA.
