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Peter Attia's Straight Dope on Cholesterol (Concept #2 – What is the…

- - - - A cholesterol ester has an “attachment” where the arrow is pointing to the hydroxyl group on carbon #3 (see fig.), i.e. the “esterification site.”
- - - - The synthesis of cholesterol is a complex four-step process (with 37 individual steps) that I will not cover here (though I will revisit), but I want to point out how tightly regulated this process is, with multiple feedback loops. In other words, the body works very hard (and very “smart”) to ensure cellular cholesterol levels are within a pretty narrow band (the overall process is called cholesterol homeostasis). Excess cellular cholesterol will crystalize and cause cellular apoptosis (programmed cell death). Plasma cholesterol levels (which is what clinicians measure with standard cholesterol tests) often have little to do with cellular cholesterol, especially artery cholesterol, which is what we really care about. For example, when cholesterol intake is decreased, the body will synthesize more cholesterol and/or absorb (i.e., recycle) more cholesterol from our gut. The way our body absorbs cholesterol is so amazing, so I want to spend a bit of time discussing it.
- - - - Beyond cholesterol’s role in allowing cells to even exist, it also serves an important role in the synthesis of vitamins and steroid hormones, including sex hormones and bile acids. Make sure you take a look at the picture of steroid hormones synthesis and compare it to that of cholesterol (above). If this comparison doesn’t convince you of the vital importance of cholesterol, nothing I say will.
- - - - Oil does not dissolve in water. It is, therefore, hydrophobic.
    - - Sugar and salt will easily dissolve in water. They are, therefore, hydrophilic.
        
        By extension, a molecule of glucose (sugar) or sodium and chloride ions (salt), because of their chemical properties which I won’t detail here, will travel through plasma without assistance. A lipid will not.
    - - A substance that has both polar/hydrophilic and nonpolar/hydrophobic properties is called amphipathic. The fact that unesterified cholesterol is an amphipathic molecule is a crucial property for its location in cell membranes.
      - Cholesterol esters in which the –OH group has been replaced by a long chain fatty acid is a very nonpolar or hydrophobic molecule.
  - - - The proteins that traffic collections of lipids are called apoproteins. Once bound to lipids they are called apolipoproteins, and the protein wrapped “vehicle” that transports the lipids are called lipoproteins.
        
        A crucial concept is that, for the most part, lipids go nowhere in the human body unless they are a passenger inside a protein wrapped-vehicle called a lipoprotein. As their name suggests lipoproteins are part lipid and part protein. They are mostly spherical structures which are held together by a phospholipid membrane (which, of course, contains free cholesterol).
        
        Apolipoproteins come in different shapes and sizes which determine their “class.” Without getting into the details of protein structure and folding, let me focus on two important classes:
        
        Apoprotein A-I (abbreviated apoA-I), which is composed of alpha-helicies, form lipoproteins which are higher in density. (The “A” class designation stems from the fact that apoA’s migrate with alpha-proteins in an electrophoretic field).
        
        Most apoA-I in our body is found on high-density lipoprotein – HDL.
        
        Conversely, apoprotein B (abbreviated apoB), which is predominantly composed of beta-pleated-sheets, form lipoproteins which are lower in density. (The “B” class designation stems from the fact that apoB’s migrate with beta-proteins in an electrophoretic field.)
        
        Virtually all apoB in our body is found on low-density lipoprotein – LDL.
        
        Going one step further, the main structural apoprotein on the LDL is called apoB100 (though we often shorten this to just “apoB”), and there is only one apoB molecule per particle.
        
        The apolipoproteins on the surface of lipoprotein molecules serve several purposes including:
        
        Acting as ligands (i.e., structures that help with binding) for situations when the lipoprotein needs to interact with a receptor on a cell.
        
        Serving as co-factors in enzymatic reactions;
        
        Assisting in the structural integrity and solubility of the lipoprotein;