As for secretion, the key point is that most low-density lipoproteins, LDL, begin their lives as very low-density lipoproteins, VLDL. (This was one implication of the observation that both LDL and VLDL are composed of the same apo B protein, and it was established beyond reasonable doubt in the 1970s.) This is why VLDL is now commonly referred to as a precursor of LDL, and LDL as a remnant of VLDL. If the liver synthesizes more cholesterol, we end up with more total cholesterol and so more LDL cholesterol, although apparently not more LDL particles. If the liver synthesizes and secretes more VLDL, we will also end up with more LDL cholesterol but we have more LDL particles as well, and they’ll be smaller and denser.

This process is easier to understand if we picture what’s actually happening in the liver. After we eat a carbohydrate-rich meal, the bloodstream is flooded with glucose, and the liver takes some of this glucose and transforms it into fat—i.e., triglycerides—for temporary storage. These triglycerides are no more than droplets of oil. In the liver, the oil droplets are fused to the apo B protein and to the cholesterol that forms the outer membrane of the balloon. The triglycerides constitute the cargo that the lipo-proteins drop off at tissues throughout the body. The combination of cholesterol and apo B is the delivery vehicle. The resulting lipoprotein has a very low density, and so is a VLDL particle, because the triglycerides are lighter than either the cholesterol or the apo B. (In the same way, the more air in the hold of a ship, the less dense the ship and the higher it floats in the water.) For this reason, the larger the initial oil droplet, the more triglycerides packaged in the lipoprotein, the lower its density.

The liver then secretes this triglyceride-rich VLDL into the blood, and the VLDL sets about delivering its cargo of triglycerides around the body. Throughout this process, known poetically as the delipidation cascade, the lipoprotein gets progressively smaller and denser until it ends its life as a low-density lipoprotein—LDL. One result is that any factor that enhances the synthesis of VLDL will subsequently increase the number of LDL particles as well. As long as sufficient triglycerides remain in the lipoprotein to be deposited in tissues, this evolution to progressively smaller and denser LDL continues. It’s this journey from VLDL to LDL that explains why most men who have high LDL cholesterol will also have elevated VLDL triglycerides. “It’s the overproduction of VLDL and apo B that is the most common cause of high LDL in our society,” says Ernst Schaefer, director of the lipid-metabolism laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. None of this, so far, is controversial; the details are described in recent editions of biochemistry textbooks.