Intracellular transport and distribution processes have a major influence on cholesterol homeostasis (A). Animal cells can obtain free cholesterol through neosynthesis in the endoplasmic reticulum (ER), in which the limiting enzyme is HMG-CoA-reductase. Cellular cholesterol can also be supplied by lysosomes, which hydrolyze exogenous cholesterol esters. Intracellular cholesterol esters (CE) also contribute to the maintenance of a pool of free cholesterol. Free cholesterol is stored in cell membranes as well as in the membranes of cell organelles. Different membranes contain different amounts of it; even within the same membrane high- and low-cholesterol regions exist. Cholesterol from exogenous sources is added to the freely available pool only when the latter is depleted below a critical limit or when membrane capacity is exceeded.
Inside cells cholesterol is subject to transportation, the regulation of which might be responsible for cellular and pathophysiological effects. Cholesterol from neosynthesis is transported from the ER to the Golgi apparatus to cell membranes inside lipid-rich vesicles in a rapid, energy-consuming process. Lysosomal cholesterol from LDL particles is probably transported by the same route. Hence, it reaches the plasma membrane quickly.
Since cholesterol is also supplied by foods, interactions between exogenous supply and endogenous synthesis are of great significance. Plasma cholesterol levels, which have been established as an independent pathogenetic risk factor, are used as a parameter. In the case of low cholesterol intake, which can only be achieved by a strict dietary regimen, the contribution of food cholesterol to total cholesterol metabolism is minor (B). Assuming 55 % absorption, the cholesterol supplied by foods makes up only 10-15% of the cholesterol used in a day. In this case, plasma cholesterol levels and LDL receptors (responsible for cellular uptake) remain in a "steady-state." The body can react to the commonly occurring increase in the supply from foods in two ways: compensate for the increased supply by reducing endogenous synthesis while maintaining a constant number of LDL surface receptors, or fail to compensate. In the latter case, the result is an increased cholesterol influx into the cells with subsequent lowering of the number of LDL receptors—leading to elevated plasma cholesterol levels.
In fact, a subsection of the population (~20-25%) reacts in this "pathological" manner to such exogenous cholesterol supply. A specific phenotype of apo-protein E has been identified as a hereditary factor involved in this reaction. Additional factors will probably be discovered as the mechanisms of cholesterol homeostasis are unraveled. To date, we are not able to distinguish compensators from noncompensators through a clinical test.
At "pharmacological" cholesterol doses, as can be achieved by dietary measures only under extreme conditions (carbohydrate-free high-fat/high-protein diets), any physiological compensation is bound to fail.
- A. Regulation of Cholesterol Homeostasis in Macrophages
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