AGE, RAGE and ALE: The ALE of LDL

I looked at glucose reacting with amino groups of proteins in the last post on the formation of AGEs. Apart from protein, cell membranes and the surface membrane of lipoprotein particles contain lipids. These form the classical lipid bilayer of biological membranes. The lipids of the bilayer come in a mix of saturates, mono unsaturates and PUFA. The exact mix of saturates to monounsaturates is largely determined by stearoyl-CoA desaturase, the enzyme which puts double bonds in to saturated fats to give monounsaturates.

Interestingly this enzyme appears to be under the control of insulin and activity goes up in insulin resistant states. That's another subject.

The PUFA composition is largely diet determined.

While boiling sugar with butter gives toffee, the situation in vivo seems more complicated and the initial generation of damaged lipids (ALEs, advanced lipoxidation end products) seems to involve an amino group. These are freely available from molecules like phosphatidylserine in cell (or lipoprotein) membranes. They provide the nitrogen for the formation of that horrible unstable Schiff base and its subsequent decay. The decaying base triggers oxidation/reduction reactions which hit double bonds in surrounding fatty acids, leading to ALE formation.

There's a good summary in this paper.

I just loved the chemistry in the introduction with stuff about electron spins, the pi antibonding level and other stuff that sounds really fancy. I think it means that molecular oxygen leaves PUFA alone without a transition metal or a pre formed free radical to get things going.

Until you add glucose that is.

Now I have two complaints about this paper. First is that some of the glucose concentrations used would make the ADA blanche. Not even an ADA diabetologist would suggest a blood glucose of 500mM (ie 500mmol/l). The 200mM used to oxidise the LDL particles would have had an intact human being in hyperglycaemic coma too. This is aggressive corner cutting on a time basis I guess. They did do some work down at 5mM.

Second is that they thanked Scott Grundy for helpful discussions. If you don't know who Scott Grundy is then you haven't read enough about the cholesterol con. Big black mark to the paper.

Third is that they used oleic acid for a lot of the work. They do comment that PUFA are 10-30 fold more oxidisable than oleic acid but PUFA didn't fit their protocols. They also forgot to mention that saturated fats just won't randomly oxidise at all in biological systems. No double bonds. But who would expect that sort of information from a cardiologist?

Did I say two complaints? Fourth...

So this paper is a bit rocky.

But what I do like about it is that it appears to show that glycation is what converts an LDL cholesterol particle in to an oxLDL particle. They're not the same. This is compatible with the recent study using low fat diets to (accidentally) raise the levels of oxLDL in intact humans.

Seems like sugar is what oxidises the PUFA in LDL to give oxLDL.

Avoid sugar, PUFA or both. Seems sensible to me.

Peter