Familial hypercholesterolemia- Case discussion

Case Details

In familial hypercholesterolemia, cholesterol is deposited in various tissues because of the high concentration of LDL cholesterol in the plasma. Of particular concern is the oxidation of the excess blood LDL to form oxidized LDL (oxLDL). The oxLDL is taken up by immune-system cells called macrophages, which become engorged to form foam cells. Which statement best describes the formation of foam cells?

A. LDL receptors on peripheral cells are upregulated

B. LDL receptors for modified LDL (Ox LDL) are not down regulated

C. LDL enters by pinocytosis to form foam cells

D. There is increased de no synthesis of cholesterol

E. Cholesterol is not extracted from macrophages by HDL

Case discussion

The correct answer is –B. LDL receptors for modified LDL (Ox LDL) are not down regulated

The liver and many extra hepatic tissues express the LDL (apo B-100, E) receptor. It is so designated because it is specific for apo B-100 but not B-48, which lacks the carboxyl terminal domain of B-100 containing the LDL receptor ligand, and it also takes up lipoproteins rich in apo E.

This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is degraded in extrahepatic tissues and 70% in the liver. A positive correlation exists between the incidence of coronary atherosclerosis and the plasma concentration of LDL cholesterol.

LDL (apo B-100, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits the transcription of the genes encoding HMG-CoA synthase—HMG-CoA reductase and other enzymes involved in cholesterol synthesis as well as the LDL receptor itself, and thus coordinately suppresses cholesterol synthesis and uptake. In this way, LDL receptor activity on the cell surface is regulated by the cholesterol requirement for membranes, steroid hormones, or bile acid synthesis, this process is called down regulation of LDL receptors (figure-1).

LDL receptor

Figure-1- Regulation of cholesterol uptake by LDL receptor. Excess of intracellular cholesterol inhibits mobilization of LDL receptors to the cell surface, this is called down regulation of LDL receptors.

The extra hepatic receptors as in case of macrophages are not down regulated for modified LDL, they keep on internalizing oxidized LDL and are eventually converted to foam cells (Figure-2)

Steps of formation of Foam cells- see the figure-2 below

1)The endothelial monolayer overlying the intima contacts blood.

2) Hypercholesterolemia promotes accumulation of LDL particles (light spheres) in the intima.

3) The lipoprotein particles often associate with constituents of the extracellular matrix, notably proteoglycans.

4) Sequestration within the intima separates lipoproteins from some plasma antioxidants and favors oxidative modification.

5) Such modified lipoprotein particles (darker spheres) may trigger a local inflammatory response responsible for subsequent steps in lesion formation.

6) The increased expression of various adhesion molecules for leukocytes recruits monocytes to the site of a nascent arterial lesion.

7) Once adherent, some white blood cells will migrate into the intima.

8) The directed migration of leukocytes probably depends on chemoattractant factors including modified lipoprotein particles themselves and chemoattractant cytokines depicted by the smaller spheres, produced by vascular wall cells in response to modified lipoproteins.

9) Leukocytes in the evolving fatty streak can divide and exhibit increased expression of receptors for modified lipoproteins (scavenger receptors).

10) There is no down regulation of such receptors.

11) These mononuclear phagocytes ingest lipids and become foam cells, represented by a cytoplasm filled with lipid droplets.

12) As the fatty streak evolves into a more complicated atherosclerotic lesion, smooth-muscle cells migrate from the media (bottom of lower panel), through the internal elastic membrane (solid wavy line), and accumulate within the expanding intima where they lay down extracellular matrix that forms the bulk of the advanced lesion.

Stages of atheroma

 Figure- Cross-sectional view of an artery depicting steps in development of an atheroma.

As regards other options in the question-

LDL receptors on peripheral cells are not upregulated.

LDL does not enter by pinocytosis to form foam cells, it is receptor mediated  endocytosis.

There is no  increased de no synthesis of cholesterol. Cholesterol is extracted from macrophages by HDL, but this is not the reason for foam cell formation.

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