Cholesterol biosynthesis enables the cells of the body to synthesize cholesterol from simple starting materials in 18 steps. This biosynthesis occurs primarily in the liver and intestinal walls. Hereditary metabolic diseases such as Tangier disease can disrupt the biosynthesis of cholesterol.
What is cholesterol biosynthesis?
Cholesterol biosynthesis enables the body’s cells to synthesize cholesterol from simple starting materials in 18 steps. The human body manufactures endogenous cholesterol in a biochemical process involving 18 different steps. This process is also known as cholesterol biosynthesis. The majority of total cholesterol is produced by the body. Only a minimal fraction is ingested through food. Cholesterol is a lipid that is essential for many bodily functions. For example, the body depends on cholesterol for steroid hormone synthesis. The same is true for various storage processes and for the construction of cell membranes. The metabolic pathway of cholesterol biosynthesis enables all living organisms with a cell nucleus to produce the important lipid from simple elements on their own. The body’s cholesterol production is regulated as needed. In the cytosol and in the endoplasmic reticulum of the cells the conversion of the substances takes place. Transcription factors regulate the processes and influence biosynthesis either positively or negatively. Bloch and Lynen received the Nobel Prize in 1964 for their research on cholesterol metabolism. Popják and Cornforth also made important contributions in the study of cholesterol biosynthesis.
Function and task
Approximately 700 milligrams of cholesterol are produced by the human body in biosynthesis day after day, and about 150 grams of cholesterol are incorporated throughout the body. Large amounts of the lipid are found primarily in the brain and adrenal glands. Cholesterol fulfills stabilizing functions in cell membranes and is thus an important building substance. In humans, cholesterol biosynthesis takes place primarily in the intestinal mucosa and the liver. Although many cells in the body are capable of synthesizing cholesterol, the liver nevertheless produces the most cholesterol. Because cholesterol from the body cannot pass through the blood–brain barrier into the brain, the brain must make its own central nervous system cholesterol. Cholesterol in the brain accounts for about 24 percent of total cholesterol. The output of cholesterol synthesis is DMAPP, which is formed in the mevalonate metabolic pathway. 18 intermediates make up cholesterol biosynthesis. Prior to synthesis, the body synthesizes acetyl-CoA. This process occurs in the mevalonate biosynthetic pathway. Via HMG-CoA, the starting material acetyl-CoA becomes mevalonic acid. The end products of the mevalonate biosynthesis pathway are dimethylallyl pyrophosphate and isopentyl pyrophosphate. Only now does actual cholesterol biosynthesis begin. The two end products of the meyalonate biosynthesis pathway are combined to form geranyl pyrophosphate. This compound is converted to farnesyl pyrophosphate. In each case, two farnesyl pyrophosphates are involved in a condensation reaction and transform to squalene as part of this reaction. This produces (S)-2,3-epoxysqualene, which in turn is converted to lanosterol. The lanosterol participates in demethylation. Thus, it becomes 4,4-dimethyl-5α-cholesta-8,14,24-trien-3β-ol. At this point, several oxidation reactions take place to give 14-demethyllanosterol. Via zymosterol carboxylate, the end products of the oxidation are converted to zymosterone. This is followed by a reduction of zymosterone yielding zymosterol. Via 5α-cholesta-7,24-dien-3β-ol, this yields 7-dehydrocholesterol. When this product is hydrogenated, cholesterol is finally formed.
Diseases and ailments
Several inherited diseases affecting the cholesterol metabolic pathway are known as familial hypercholesterolemias. Irrespective of diet, severely elevated plasma cholesterol levels are present in these disorders. Vascular diseases and heart attacks can develop at an early age as secondary diseases. The disease is caused by a defect in the gene that codes for the LDL receptor. Because of this defect, the LDL receptor is formed only incompletely or not at all. The LDL level of affected individuals in particular is therefore significantly elevated. Xanthomas characterize the clinical picture.These are fatty deposits in the skin, internal organs and central nervous system. Hypercholesterolemia does not have to run in families, but can also be acquired. Acquired forms are mainly triggered by malnutrition. Diabetes can be the primary disease. Obesity or chronic renal insufficiency are also often associated with elevated cholesterol levels. In addition to diets, drugs such as CSE inhibitors are used to treat above-average cholesterol levels. Statins can inhibit cholesterol biosynthesis. This inhibition is targeted by treatment with CSE inhibitors. They prevent HMG-CoA reductase and thus enable a general reduction in serum cholesterol concentrations. In this way, for example, the secondary disease arteriosclerosis can be slowed down. CSE inhibitors can also prevent cholesterol-related heart attacks or other concomitant diseases associated with high cholesterol levels. Hypocholesterolemias are the opposite of hypercholesterolemias. Low serum cholesterol, as occurs in hypocholesterolemias, is related to malignant cancer in a majority of cases. In carcinoma-related hypocholesterolemia, the lowered cholesterol level is usually evaluated as a risk factor for all-cause mortality. Malnutrition, AIDS, or severe infections are other causes of severely low cholesterol levels. However, hypocholesterolemia can also occur as part of a hereditary disease. An example of such a disease is Tangier disease. Patients with this disease suffer in particular from HDL hypocholesterolemia.
