Familial Hypercholesterolaemia and porcelain

What IS an LDL particle? There is a very neat picture here. Perhaps the most striking thing about it is that there is only one single protein molecule embedded in the particle surface, the apo-B100 protein molecule. It wraps neatly around the sphere of lipid to give support and identity. Identity is very important.

Of course the LDL particle has to come from somewhere. It is derived from IDL (Intermediate Density Lipoprotein) and before that from VLDL (Very Low Density Lipoprotein), which was secreted by the liver. All of these precursors also have the apo-B100 protein molecule, plus a whole load of other proteins too, apo-C1, apo-C2, apo-C3, and apo E. VLDLs are big (relatively), they need to be to fit all those proteins on to their surface! Most of these proteins are there to either turn on or turn of lipoprotein lipase, in order to get fatty acids from the lipid particle in to cells. That's how lipids get bulk transported. Apo-E gets the particle back in to the liver, should the liver want it back.

Quite where all of these proteins disappear to as LDL is formed is a bit of a mystery to me. Certainly it looks like LDL, derived from IDL/VLDL, has only apo-B100 and none of the other surface proteins of VLDL/IDL particles. Probably they hop on to HDL particles. Some of them came from there in the first place, rather than the liver directly, so that would be appropriate.

So there is this bag of lipid with just one identification tag on its surface, looking for a home. There is a receptor which exactly fits the apo-B100 id tag. The LDL cholesterol receptor. This is the archetypal, best studied endocytosis receptor of all time. LDL attaches to this receptor and the whole lipoprotein is engulfed by the cell sporting the receptor. The particle gets stripped of the engulfing apparatus, eventually fused with a lysosome and the cell is in clover with a supply of both lipid and cholesterol. It recycles the LDL receptor to the cell surface and does it all again. Cells appear to need both lipid and cholesterol.

But here's the interesting bit. The LDL receptor is a statin as in:

"Consistent with this hypothesis, they found that addition of LDL to the culture medium of normal human fibroblasts inhibits the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme in the cholesterol biosynthetic pathway

EDIT: When you go to the original authors it becomes obvious that it is the cholesterol itself which inhibits HMG-CoA, a classic negative feed back mechanism. Have to do some more thinking about xanthomata. End edit.

The LDL receptor inhibits the intracellular synthesis of cholesterol, at the HMG-CoA step, when activated by an LDL particle. There is impeccable logic to this. Cholesterol is a complex molecule, synthesised in a stupendously intricate and energy demanding process. Usually the liver does this for cells of the body, shipping it out in lipoprotein particles. After all the liver is a biosynthetic powerhouse with lots of energy to play with. It's not some poor smooth muscle cell or fibroblast struggling to make metabolic ends meet in the arterial media. If, as a cell, you have just swallowed a big ball of cholesterol you can afford to switch off the production apparatus. It would be wasteful not to.


Cells need cholesterol. Homozygous familial hypercholesterolaemia means that a patient's cells have zero functional LDL receptors. If they can't get cholesterol by swallowing whole LDL particles they really do have to make it themselves. But the other feature of a non functional LDL receptor (remember, it's a statin) is that it doesn't give the ability to limit local cholesterol synthesis, so there might be quite a lot of cholesterol made. Enough to generate tendon xanthomas. These xanthomas should be composed of cholesterol synthesised from acetate in local cells, not from sticky LDL particles. I don't suppose anyone has checked this.

The synthesis of one molecule of cholesterol requires 14 NADPH molecules and 18 ATPs. It yields 6 phosphate (Pi) molecules and 4 pyrophosphate (PPi) molecules. While PPi appears to be an inhibitor of soft tissue calcification Pi is a promoter. Alkaline phosphatase, an enzyme whose production is upregulated by hyperglycaemia, converts PPi (calcification inhibitor) to Pi (calcification promoter). Hyperglycaemia is a feature of refined carbohydrate diets. Did I say low fat?

So there is the potential for an awful lot of inorganic phosphate ions, possibly 14 per molecule, being produced as a spin off from cholesterol synthesis on low fat diets. One LDL particle provides about 2000 molecules of cholesterol.

We know that insulin converts smooth muscle cells to bone secreting cells. Local cholesterol synthesis provides a supply of inorganic phosphate. A low fat (high sugar) diet raises insulin.

Perhaps it should come as no surprise that there is the phenomenon of "porcelain aorta", seen in patients with homozygous familial hyprecholesterolaemia. Aortic cells manufacturing cholesterol, which they can't get from LDL, produce inorganic phosphate and pyrophosphate as a spin off from the synthesis. A modern low fat diet, based on sugar, elevates blood glucose which increases alkaline phosphatase production and so the conversion of pyrophosphate to inorganic phosphate. A modern low fat diet elevates insulin too, which makes smooth muscle cells secrete bone matrix proteins.

Add calcium to phosphate in soft tissues and you have bone.

How good is the evidence base for current dietary recommendations in Familial Hypercholesterolaemia, particularly in children, who don't seem to get put on a pharmaceutical statin (yet)?

The Cochrane Review seems to think they are completely unsubstantiated.

Should all homozygous FH people be on a pharmaceutical statin? Another post there.

Peter


NB I didn't see any calcium or phosphate in that picture of the LDL particle. Soddy: "Rutherford, this is transmutation!" Rutherford snapped back, "For Christ's sake, Soddy, don't call it transmutation. They'll have our heads off as alchemists." Or cardiologists.