Metabolism of lipids and lipoproteins
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Chylomicrons

Chylomicrons (particles very rich in triacylglycerols) are formed in the cells of the Small Intestine mucosa by absorption of dietary fat. The condition for the secretion of chylomicers from the cisterna Golgi apparatus of enterocytes is the presence of apolipoprotein B48 (=ApoB48). This apolipoprotein contains only 48% of the peptide molecule of liver apolipoprotein, which is therefore referred to as ApoB100 (i.e. 100% peptide chain).

After 12-14 hours of fasting, chylomicrons are no longer normally present in the blood plasma. They are immediately hydrolyzed upon entering the blood capillary bed by the action of endothelial lipoprotein lipase (LPL) to form chylomicron remnants (chylomicron remnants). During the lipolytic action of these enzymes, fatty acids are released.

Some components of chylomicrons (apoA-I, apoA-II, apoC, and phospholipids) are transferred to HDL particles, and other components (apoE and cholesterol esters) are transferred from HDL to chylomicrons. Chylomicron remnants containing apoB48 and apoE are taken up by their receptors in the liver. The formation of these receptors in liver tissue cells is regulated by the amount of cholesterol and fat in the diet. Their activity decreases with age. ApoE facilitates the uptake of chylomicron debris, while apo C-III inhibits this process. The physiological importance of chylomicrons lies in the delivery of fatty acids from food to adipocytes and muscle cells.

VLDL

Metabolism of VLDL

VLDL synthesis occurs in the liver and is more intense in obese individuals. It is regulated in part by diet and hormones and is inhibited by uptake of chylomicron debris in the liver. By the action of lipoprotein lipase (LPL) located on the membrane of endothelial capillaries, with the participation of apoC-II as a cofactor, triacylglycerols carried by VLDL particles are hydrolyzed to be available in the respective cells as an energy source or for storage in the form of storage triacylglycerols. In this process, some components from VLDL (apoE, apoC) are transferred to HDL, while apoB100 remains on VLDL-remnants (VLDL-remnants or intermediate lipoprotein particles = IDL). The final product of VLDL catabolism is LDL.

Under pathological conditions (in some patients with severe hypertriacylglycerolemia), VLDL are removed from the blood plasma without being converted into LDL particles. The liver produces different types of VLDL-particles: On a low-fat diet, these are particles of Sf 60-400, which are larger and non-atherogenic; with a diet rich in fats, mainly small dense VLDL with Sf 12-60 are formed, which, on the other hand, are very atherogenic., small dense LDL-B is formed from them.

The receptor for lipoprotein "remnants" (VLDL remnants and chylomicron remnants) is the so-called protein related to the LDL receptor (=LDL receptor related protein). The specific ligand is Apo E Lipoprotein lipase (=LPL), which catalyzes the cleavage of fatty acids from triacylglycerols in chylomicrons and VLDL, is in the surface part of endothelial capillaries mainly in adipose tissue and muscle, where it is necessary for the formation of storage triacylglycerols and for the utilization of fatty acids as an energy source. The activator is Apo CII. Insulin does not directly affect LPL activity but is needed to maintain it. On the other hand, the so-called hormone-sensitive lipase (=HSL), which hydrolyzes intracellular triacylglycerols (released fatty acids enter the blood circulation and linked to albumin to the liver), is influenced by insulin directly, in the sense of inhibition. Glucagon, on the other hand, stimulates its activity. Thus, after a meal, insulin supports the storage of fatty acids in adipocytes, and conversely, during starvation, they are released into the circulation and absorbed in the liver and muscles.

LDL

LDL receptor

LDL are the main particles that carry cholesterol in the blood plasma. The largest part comes from the transformation of VLDL, but some is synthesized directly (especially in patients with familial hypercholesterolemia). The main protein component of LDL is apoB100. LDL can be catabolized by different cell types, both by an ``LDL-receptor-dependent mechanism and by an LDL-receptor-independent mechanism ("scavenger" mechanism).

After binding to the membrane receptor (its duration is 5-7 minutes), the LDL particle is internalized and broken down by the cell. The resulting free cholesterol inhibits the activity of 3-hydroxy-3-methylglutaryl-CoA-reductase, which is a key enzyme for the synthesis of (de novo) cholesterol in the cell. In this way, "cholesterol synthesis is controlled according to the needs of the cells". LDL not captured by peripheral cell receptors (about one third) are catabolized by "sweeping" (=scavenger) cells. However, this method is not driven by the needs of the cells. Some LDL is also metabolized in the liver. The released cholesterol is either catabolized to bile acids and excreted into the bile, or is reused for lipoprotein synthesis.

Oxidized LDL particles are "pathological" particles, strongly atherogenic, which arise from the oxidation of conjugated double bonds in fatty acids by the action of free oxygen radicals. Oxidation of LDL is positively correlated with the content of polyunsaturated fatty acids (PUFA) and, conversely, negatively with the content of monounsaturated acids in lipoprotein particles, as well as with the content of ubiquinol (=coenzyme Q10) and non-esterified cholesterol. Ubiquinol inhibits the early stage of LDL oxidation and is significant as the first antioxidant that scavenges free radicals. Other substances preventing the oxidation of LDL are flavan-3-ols, β-carotene (last protection). Non-esterified cholesterol reduces the fluidity of the particle surface and thus inhibits the diffusion of free radicals into the interior of the particle. On the contrary, oxidation is accelerated by Cu, Fe, Ni, Cd, as well as a lack of Mg, as well as light.

Small dense LDL-B are more easily oxidizable than larger LDL-A, which have a higher antioxidant content. Oxidation of LDL particles probably does not occur in the blood plasma, which contains a lot of antioxidants and substances that bind metal ions required for the Fenton reaction, but in the arterial wall, where oxidative stress can occur more easily. Oxidized LDL are highly atherogenic because they are not taken up by LDL-receptors, but by receptors of "sweeper cells" and thus contribute to the formation of foam cells of atheroma plaques. Frequent states of persistent hyperglycemia leading to increased formation of glycated proteins (ie also lipoproteins) stimulate the oxidation of LDL. Advanced glycation end products (AGE = Advanced Glycosylation End products) are also created, which form cross links with LDL particles, which are then more easily oxidized.

HDL

HDL particles are synthesized in hepatocytes and enterocytes. Since their inception, they have gone through several stages of development; They enter the blood in the form of a precursor called nascent HDL. These are discoid in shape and consist only of bilayers of phospholipids and Apo A I, Apo A II, Apo C and Apo E. Nascent HDL are acceptors. non-esterified cholesterol, which originates from the cell membranes of various tissues or from the surface structures of other blood lipoproteins. On the surface of the HDL particle, cholesterol is esterified under the catalysis of the enzyme lecithin:cholesterol acyltransferase (LCAT). The activator is Apo A I, Apo C I and perhaps Apo A-IV. By the accumulation of cholesterol esters, the discoid particle is transformed into spherical - HDL3. By further accumulation of cholesterol esters, HDL3 changes to HDL2. In the serum of healthy individuals, the ratio of HDL3/ HDL2 is 2: 1 to 3: 1. HDL particles undergo a cyclic transformation when interacting with lipoproteins rich in triacylglycerols: HDL 3 is transformed into HDL2a by the accumulation of cholesterol esterssub>; it changes to HDL2b by exchanging cholesterol esters for triacylglycerols. This exchange mainly involves VLDL particles and chylomicrons, which gradually change to remnant particles (IDL or chylomicron remnants). The exchange is mediated by a specific protein: CETP (=Cholesterol-Ester-Transfer-Protein). HDL2b particles enriched with triacylglycerols are again transformed into HDL3 by lipolysis of triacylglycerols and phospholipids by the effect of liver triacylglycerol lipase (=HTGL). Apo A II acts as an activator.

Cholesterol esters in VLDL and chylomicron remnants enter the liver via two routes:

  1. by the uptake of remnant particles by the receptor for Apo B/E on hepatocytes
  2. indirectly via IDL, which undergo further hydrolysis in the liver by the effect of liver triacylglycerol lipase and change to LDL. 2/3 of these are absorbed in the liver via LDL receptors; only 1/3 ends up in peripheral cells, where they are captured by LDL-receptors.

In addition, it is believed that whole HDL particles can be taken up by hepatocytes and degraded, so that cholesterol from peripheral tissues ends up in the liver by this route as well. HDL particles thus play a key role in the so-called reverse transport of cholesterol, which enables the removal of excess cholesterol from peripheral tissues and from lipoproteins of other classes back to the liver, which is the only organ capable of breaking down cholesterol (into bile acids) and excreting it from the body via bile. This prevents the accumulation of cholesterol in the macrophages in the artery wall. and the development of atherosclerosis slows down.

Metabolic relationships between HDL and triacylglycerols.

Particles rich in triacylglycerols (VLDL, possibly IDL, chylomicrons, chylomicron remnants, LDL-B) and high-density lipoproteins (HDL) exchange their components with each other: apolipoprotein E and C and cholesterol esters are transported from HDL; on the other hand, part of the triacylglycerols from VLDL (possibly other lipoproteins rich in triacylglycerols) is transferred to HDL. This interaction is influenced by LCAT and CETP; CETP activity is also influenced by the concentration of fatty acids released during VLDL lipolysis, especially in conditions leading to hypertriacylglycerolemia. Increased CETP activity leads to a decrease in HDL-cholesterol. This increased CETP activity has been demonstrated, for example, in smokers or obese patients, where a drop in HDL-C is a typical finding. CETP activity normalizes when smoking is stopped or excess weight is reduced. The undisputed decisive factor in the regulation of esterification and remodeling (transformation of HDL2a → HDL2b) of HDL particles and thus also in the regulation of HDL-C levels is the concentration of triacylglycerols in the plasma. The initial cause of the drop in HDL-C in hypertriacylglycerolemia is probably the level of free fatty acids (=VMK). A typical example is ``metabolic syndrome X (Reaven): Insulin resistance leads not only to impaired glucose entry into cells but also to impaired VMK entry into adipose tissue. The increased plasma concentration of VMK then leads to their increased absorption in the liver, where new triacylglycerols are formed from them, which are then incorporated into VLDL and excreted into the circulation. As a result of insulin resistance (and thus hyperinsulinemia), LPL activity is inhibited, which is another cause of persistent hypertriacylglycerolemia. However, it is not only a quantitative change in the amount of synthesized VLDL, but also a change in the quality of VLDL; instead of "normal" VLDL with Sf 60 - 400, atypical VLDL is formed, very rich in triacylglycerols, which are additionally resistant to the effect of LPL. Atypical VLDL are converted to very atherogenic dense particles (="small dense LDL") with a concomitant decrease in HDL-C. A high concentration of atypical VLDL very rich in triacylglycerols leads to an increased exchange of triacylglycerols for cholesterol esters with HDL particles by the effect of CETP; this causes gradual depletion of cholesterol in HDL particles.

A certain part of the lipoprotein particles (especially when they are increased in the plasma or when their composition is abnormal, e.g. as a result of lipoperoxidation), are taken up by the so-called "sweeping" cells ("scavenger cells", i.e. macrophages and RES histiocytes) through special receptors, forming foam cells. This process is not regulated according to the cholesterol content in the cells and can be associated with the formation of xanthoma, with lymphadenopathy or with hepatosplenomegaly.

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