Molecular Nutrition coursework

I threatened it, then I thought better of it, and now the threat comes true: a post about microsomal triacylglycerol transfer protein (MTP). You lucky, lucky readers.

This is for my benefit, not yours, of course. I don't imagine anyone who might read my blog would be even passingly interested in this obscure enzyme, but today my essay has to be finished. It is taking longer than is plausible, so writing down what I know at this point might just crystallize my knowledge and allow me to finish the damn thing a bit quicker.

What MTP does is to take the molecules of fat that we've eaten and digested and absorbed, and shuttle them into structures called lipoproteins. Because fat is insoluble in water, and therefore doesn't dissolve in blood, it must be transported around the body in a form that is soluble, which is what the lipoprotein is. (You will have heard of at least two sorts of lipoprotein: LDL and HDL, which are low-density and high-density lipoproteins. HDL is the one we need more of; LDL is the undesirable one.)

A lipoprotein is formed from a membrane 'shell' that is made of the same stuff that all our other cell membranes are made of (phospholipid and cholesterol), and contains lipid (fat) molecules and more cholesterol attached to lipid. (If we take up too much cholesterol it ends up in LDL, and this is a Bad Thing because it finds its way into artery walls and causes atherosclerosis, thrombosis and heart attacks. HDL is a Good Thing because it travels round the body picking up cholesterol and delivering it back to the liver, out of harm's way).

So MTP hooks up to a protein called apolipoprotein B (apoB) attached to a bit of membrane, and scoops up lipid (triacylglycerol) and shoves it inside the membrane, filling up the lipoprotein. Hence 'triacylglycerol transfer protein' - 'microsomal' just tells us where it is located.

So far, so good. The essay I have to write is about gene polymorphisms in lipoprotein metabolism. In real words, this means it's about any differences between the DNA code for MTP that make a difference to its effect on lipoproteins in the body.

A gene is just a string of DNA 'code' that is represented by four letters: C, G, A and T. Inside a cell, the DNA code is transcribed into RNA and then translated into amino acids to make a protein. There are a number of different regions in a gene: a region indicating where it starts, where it ends, and a preliminary bit called a 'promoter'. Turning genes 'on' and 'off' is often done in the promoter region - something binds to the DNA promoter that prevents the gene being decoded and turned into protein, for example.

In the gene promoter for MTP, there's a polymorphism. This means that in a proportion of people, at position 493 the string of DNA code contains the letter G, but in others it's a T - the official name is MTP -493G/T polymorphism. Because we've got two copies of every gene, we might have combinations GG, GT or TT. All are good enough for the decoding to go ahead and make MTP, but it turns out that if you've got the letter G, it isn't quite as good as if you've got a T.

[Just writing this has already highlighted something I need to clarify: MTP is actually made of two proteins linked together... I need to clarify which of the two genes I'm talking about in my essay. And just for interest, if your version of MTP is seriously garbled, you get something called abetalipoproteinaemia, in case you fancy looking it up. OK, move on.]

The main trouble is that there are literally millions of different factors that affect gene transcription and translation - some are other gene combinations (e.g. our ethnic background), and some are 'environmental' - how much fat we eat, how much exercise we do, whether we smoke or drink alcohol, even our income and where we live have an indirect effect. The researchers try very hard to separate out the genetic factors from everything else, matching their experimental group with people who are similar in every respect except the G/T polymorphism. This is, of course, impossible, but if experiments are done on enough people, statistical trends should emerge.

The work I'm looking at has focussed on two different diseases: non-alcoholic steatohepatitis (NASH), and diabetes. NASH is a disease of the liver, where an accumulation of fat has progressed into more serious symptoms, sometimes resulting in cancer. You will have heard of diabetes, where either the pancreas isn't producing insulin in response to glucose, or the insulin it does produce isn't dealing effectively with the glucose.

They think there is a link between NASH and diabetes - having one condition predisposes a person to getting the other. The research about the MTP G/T polymorphism has been looking at whether MTP has an effect on something that then causes both NASH and diabetes. The research suggests that it might be that the GG version of MTP (two copies of the gene with G at position 493) has an effect on two types of lipoproteins (resulting in more oxLDL and less HDL-C), and that these not only affect the liver but also pancreatic beta-cells, which are the ones that produce insulin.

That's it. I suspected it wasn't a very interesting choice of topic, and now that I've written it down, I can see that it really isn't a very interesting choice of topic. Too late now. This has helped, so that's good. But I still don't know why MTP isn't called MTTP...