The Cholesterol Paradox, Part I


Here is the quote from the above diagram from Metabolic Regulation: A Human Perspective by Keith N. Frayn, regarding cholesterol regulation (emphasis added):

The full length SREBP protein is located in the ER. It is associated with the SREBP cleavage activating protein (SCAP), which “senses” the level of cholesterol, or related sterols, within the membrane of the ER. When the cholesterol content is low, the SCAP-SREBP complex migrates to the Golgi complex, where specific proteases cleave SREBP to release the N-terminal portion, “mature” SREBP. Mature SREBP moves to the nucleus where it binds to sterol response elements in the promoter regions of many genes. If SREBP-2 is concerned (as shown in the figure), these are mainly genes concerned with cholesterol metabolism (LDL receptor, enzymes of cholesterol synthesis). SREBP-1 appears to be regulated more by expression of the full-length protein (which is increased by insulin); its proteolytic cleavage is also stimulated by insulin independently of cholesterol. SREBP-1c increases the expression of genes concerned with fat storage.

In sum: modern methods of dieting to lower cholesterol levels don’t make much sense in light of the body’s ability to regulate cholesterol synthesis. Even with this, the contribution of cholesterol synthesis to the total cholesterol store in the body is small. A good analogy to describe this is the “pool” analogy in this video by Dr. Peter Attia (between 7:20 – 8:10 minutes):

As he suggests, the total store of cholesterol in the body is akin to a giant swimming pool, and there are two very small hoses contributing to the swimming pool: an internal hose (cholesterol synthesis) and an external hose (cholesterol input from diet). As he states, anything in biology that resembles this situation, with a large store of something with two very small contributing inputs, suggests that the system is highly regulated and that what is moving the “cholesterol needle” isn’t the small inputs (diet and internal synthesis) but something else…


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