The low-density lipoprotein receptor pathway
The incontrovertible link between plasma cholesterol and CHD is directly responsible for the rapid growth, and occasional quantum leaps, in our understanding of cholesterol homeostasis in relation to diet and disease, the most prolific of which was the discovery of the LDL receptor pathway by the Nobel Prize winners Goldstein and Brown (1977) (Figure 6.8).
All cells, most notably those in the liver, have a highly developed and sensitive mechanism for regulating intracellular and intravascular levels of cholesterol. Cells in the liver synthesize approximately 500 mg of cholesterol a day and, although they can import the same quantity from the blood in the form of LDL, in the complete absence of LDL, cells could theoretically manufacture sufficient cholesterol to meet their met-abolic needs. However, when stressed, cells will always import cholesterol in preference to synthesizing it themselves as the former process takes less energy. Cells acquire cholesterol from the blood by the uptake and degradation of LDL particles. As the requirement for free cholesterol increases within the cell, it increases its production and thus activity of LDL receptors, so that more LDL is extracted from the blood, lowering blood cholesterol. Conversely, if the cell becomes overloaded with cholesterol, it senses that it requires less cholesterol and produces fewer LDL receptors, causing blood cholesterol to increase. Since the pro-duction of LDL receptors is regulated by the intracel-lular level of free cholesterol, anything that increases free cholesterol within the cell will inadvertently lower blood LDL cholesterol. Intracellular free cholesterol represses the activity of a sterol regulatory element binding protein (SREBP), a positive nuclear tran-scription factor that promotes the transcription of the LDL receptor gene when free cholesterol levels fall.
The metabolic effects of intracellular free cholesterol are:
● it decreases the production of LDL receptors via SREBP
● it inhibits the synthesis of cholesterol by the enzyme 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase
● it increases the re-esterification of cholesterol for storage as cholesterol esters.
Goldstein and Brown were aided in the discovery of the LDL receptor by studying a condition known as familial hypercholesterolemia, a genetic abnormal-ity in the LDL receptor gene that produces defects in the LDL receptor pathway and considerably elevated blood cholesterol concentrations in early life (15– 20 mmol/l) and premature cardiovascular disease. They also initiated pioneering studies on the influ-ence of dietary fats on the activity of the LDL pathway, which led to a widely accepted explanation for the cholesterol-raising properties of saturated fatty acids.
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