Hypolipoproteinemias: Tangier disease
A decrease in blood lipoprotein levels is a rare phenomenon. A striking example is Tangier disease. It is caused by a genetic defect in the ABC1 protein, which normally transports cholesterol from cell membranes to high-density lipoproteins (HDL).
Due to this defect, HDL levels drop to 1–5% of normal, the number of low-density lipoproteins (LDL) also decreases, and generalized hypocholesterolemia develops. Cholesterol cannot leave the cells and begins to accumulate in tissues. This leads to enlargement of the liver and spleen (hepatosplenomegaly), as well as damage to nerve sheaths (neuropathy) due to lipid accumulation in Schwann cells.
Classification of hyperlipoproteinemias
Elevated blood lipoprotein levels are classified into several types depending on the genetic defect and changes in the lipid profile:
- Type I (Familial chylomicronemia syndrome): Caused by a defect in lipoprotein lipase or apolipoprotein CII. Chylomicrons and VLDL accumulate in the blood, and triacylglycerol levels rise. There is no risk of atherosclerosis.
- Type II (Familial hypercholesterolemia): Associated with an apoB-100 gene mutation or an LDL receptor defect. Characterized by high LDL concentrations and hypercholesterolemia. Leads to premature atherosclerosis and xanthomatosis.
- Type III (Familial dysbetalipoproteinemia): A defect in apoE structure (synthesis of the apoE₂ isoform that fails to bind to receptors). Blood levels of remnant chylomicrons, VLDL, IDL, and LDL increase. Early atherosclerosis is also characteristic.
- Types IV and V (Familial hypertriacylglycerolemia): A heterogeneous group often associated with overproduction of VLDL in the setting of hyperinsulinemia. Accompanied by elevated VLDL, LDL, triacylglycerols, and an increased risk of atherosclerosis.
Risk assessment and pathogenesis of atherosclerosis
An excess of atherogenic lipoproteins (especially in the presence of LDL receptor mutations, lipid peroxidation, and a high-calorie diet) leads to the formation of an atherosclerotic plaque. It damages the inner lining of arteries, disrupts blood flow, and serves as a substrate for thrombus formation. The ultimate outcome is myocardial infarction or stroke.
To assess risk, the atherogenic index is used, calculated from a fasting blood test:
(Total Cholesterol - HDL Cholesterol) / HDL Cholesterol
Normally, this indicator should be less than 3.5. The higher it is, the greater the likelihood of developing atherosclerosis.
Free cholesterol and its esters
Cholesterol in the body exists in free form and as esters. Free cholesterol is amphiphilic, allowing it to integrate into cell membranes. It serves as a substrate for bile acids in the liver and regulates its own synthesis by acting as a corepressor of the HMG-CoA reductase gene.
Cholesterol esters are the stored and transport form. They are formed in the intestine (by the enzyme ACAT for packaging into chylomicrons) and in the blood (by the enzyme LCAT as part of HDL). Esters form the core of particles such as LDL and VLDL and are stored in cells as lipid droplets.
Pharmacotherapy
Several classes of drugs are used to correct dyslipoproteinemias, each with a specific site of action:
- Statins (HMG-CoA reductase inhibitors): suppress cholesterol synthesis in the body, forcing cells to take it up from the blood more actively.
- Bile acid sequestrants: bind bile acids in the intestine, interrupting their enterohepatic circulation. The liver is forced to use more blood cholesterol to synthesize new acids.
- Niacin (nicotinic acid): inhibits lipolysis in adipose tissue, which reduces VLDL production.
- Fibrates: stimulate receptors, increasing the synthesis of lipoprotein lipase and apolipoproteins A-I/A-II. This lowers triacylglycerol levels and raises protective HDL.
Briefly: answers to topical questions
Which cells take up modified LDL and transform into foam cells during atherogenesis?
Modified low-density lipoproteins are taken up by macrophages, which then transform into foam cells. This process occurs after LDL undergoes modification (such as lipid peroxidation or protein glycosylation) and becomes "foreign" to the body. Cholesterol-laden foam cells penetrate the vascular intima through the endothelium. The destruction of these cells and the accumulation of cholesterol in this area represent the initial stage of atherosclerotic plaque formation.
Which lipoprotein fractions are strictly atherogenic?
Atherogenic fractions include all lipoprotein classes containing apolipoprotein B-100, as they transport cholesterol from the liver to peripheral tissues. Depending on their ability to cause atherosclerosis, the following fractions are distinguished:
- Very low-density lipoproteins (VLDL) — synthesized by the liver and released into the bloodstream.
- Intermediate-density lipoproteins (IDL) — formed from VLDL under the action of endothelial lipoprotein lipase.
- Low-density lipoproteins (LDL) — the main carriers of cholesterol to tissues.
What is the physiological function of apolipoprotein C-II in lipoprotein metabolism?
The physiological function of apolipoprotein C-II is to activate the enzyme lipoprotein lipase. Lipoprotein lipase, located on the surface of the vascular endothelium, "recognizes" chylomicrons via interaction with apoC-II and hydrolyzes the triacylglycerols within them into glycerol and free fatty acids. Immature chylomicrons acquire apoC-II in the bloodstream from high-density lipoproteins, leading to the formation of mature particles. After the hydrolysis of most triacylglycerols, remnant chylomicrons are formed, which lose apoC-II by returning it to high-density lipoproteins.
Class and exam questions
What does the atherogenic index show?
It reflects the ratio of "bad" and "good" cholesterol in the blood. A value above 3.5 indicates an increased risk of developing atherosclerosis.
Why is there no risk of atherosclerosis in Type I hyperlipoproteinemia?
In Type I, massive particles—chylomicrons—accumulate in the blood. Due to their large size, they cannot penetrate the vascular wall and form atherosclerotic plaques.
What is the difference between free cholesterol and its esters?
Free cholesterol is a structural component of membranes and a precursor to bile acids. Cholesterol esters serve as a form for safe transport (inside lipoproteins) and storage as lipid droplets.
What else to study on this topic
- Mechanism of enterohepatic circulation of bile acids
- Structure and functions of apolipoproteins (ApoB-100, ApoE, ApoC-II)
- Role of lipid peroxidation (LPO) in atherogenesis
- Impact of dietary factors (trans fats, carbohydrates) on the lipid profile
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