AGE RAGE and ALE: segregation

Both glucose and fructose are transported from the gut to the liver via the portal vein. I've never seen papers which have measured the concentration of either of these sugars in the portal vein, but the determinants must be rate of uptake from the gut, strongly influenced by dietary load, and splanchic blood flow, a high flow carrying the sugars at lower concentration per unit uptake. Ultimately this blood flow must carry the highest plasma glucose concentration and absolutely the highest plasma fructose concentration in the body, especially in the aftermath of drinking a giant Pepsi. Or maybe after a detox dose of Kiwi fruits.

Fatty acids come as mixtures. Even beef dripping carries a small load of PUFA. Nuts more so, seeds like those from Sunflowers much more so. Humans eat all of these in variable quantities. They are broken down by lipase, absorbed in to intestinal cells and reassembled in to triglycerides to be secreted as chylomicrons. Chylomicrons are the bulk transport system used to get lipid, including the PUFA, from the diet to the muscles, fat and the liver. A chylomicron is labled with a marker protein. It's a truncated form of that good old apoB100 used by the liver to mark the VLDLs destined to become LDL particles. The truncated protein is called apoB48. It starts life as an apoB100 but gets a socking great chunk cut off between transcription and particle assembly. It looses the LDL receptor interacting section but keeps the AGE triggered switch. No one seems to have looked at how glycation of chylomicrons acts in terms of receptor attachment to deliver lipid to muscles, or it's interaction with the "LDL-like" receptor which allows it to be recycled by the liver. I'll bet both actions get mangled by glycation. It does seem reasonable to assume that glycation allows chylomicrons to interact with RAGE, the receptor for glycated lipoproteins on mesothelial cells, in particular macrophages. These are the cells which make foam cells as part of atherosclerotic lesions.

This seems to be a feature of all apoB containing lipoproteins which have been glycoxidised. Obviously you would expect this to be a problem in the chronic hyperglycaemia of diabetes.

If your dietary carbohydrate intake stays within the capability of your liver to handle effectively, avoiding systemic hyperglycaemia, there is no need for foam cell formation. Avoiding chylomicron glycation under these physiologically normal circumstances, ie when you don't need foam cells, is likely to be beneficial. That's what happens.

The body actually puts chylomicrons in to the lymphatics which drain the gut, not in to the portal vein. They then pass down the thoracic duct and directly in to the venous circulation, avoiding the portal vein and its glycating environment. Mixing bulk lipids with bulk sugars gives bulk glycoxidation. Evolution has segregated them.

I'd always wondered why the digestive system was arranged this way. Now at least I have some idea.

Peter