Sunday, December 14, 2008

Cholesterol and innate immunity

You would be forgiven for thinking that the apoB100 protein (which defines the LDL or VLDL particle) has been evolved over the past 4.5 billion years to cause cardiovascular disease and the less of it you have the longer you will live. Listening to a cardiologist that is (or a BBC reporter on the Today Program grovelling before a cardiologist). The lower the better. It's impossible to have too low an LDL concentration. Statins in the drinking water. You know the patter.

Until you go in to hospital that is. Do you want an MRSA infection?

The apoB100 protein and its LDL particle are part of the innate immune system. OK, financial declaration time: Our household is 50% funded by the tail end of a PhD grant for a thesis on the innate immune system. If the post doc grant does not come through we're in big trouble. So the innate immune system REALLY matters. To us anyway.

Once upon a time you died in the ICU of overwhelming pseudomonas infection. Nowadays it's MRSA. Methycillin resistant staphylococcus aureus is an ubiquitous and mostly pretty harmless bug, unless you get ill. Then you can get in to serious trouble with it. Or maybe not... so what decides whether you live or die?

MRSA has a switch in its DNA which controls 4 genes that determine whether it sits on the skin surface as a virtual commensal or invades the tissues as a pathogen. One of these genes codes for a signalling peptide called AIP. In fact there is a choice of four different AIPs, AIP 1 being the one possessed by many particularly nasty clinical isolates of MRSA. AIP 1 is essential for the virulence of the bug and it is bound by the apoB100 protein. This binding is particularly effective when the protein is where it belongs, sitting on the surface of an LDL or VLDL particle. What seems to happen is that the AIP 1, which is lipid soluble, ends up in the lipid centre of the lipoprotein. In the mele of an acute infection the LDL particle becomes oxidised and so gets eaten, along with its AIP 1 burden, by a macrophage. Thus endeth the virulence factor of the MRSA, unless you have particularly low LDL or VLDL lipoprotein levels. In which case you are in big trouble.

Of course your death in the ICU from an MRSA infection is of no concern to your cardiologist, after all, it wasn't due to a heart attack... The lower the better etc etc etc

The abstract of the AIP paper is here if you fancy a read.

Statin premed anyone?

Peter

6 comments:

darwinstable said...

I know all about the desperate need for post doc funding

Peter said...

Hi Dan,

There is a huge drive to get vets to go in to research, they tend to be quite good at it. Once you are there you tend to wonder quite what the **** you can do next. Answers on a post card to...

TedHutchinson said...

As cholesterol is a precursor to vitamin D, inhibiting the synthesis of cholesterol must also affect the synthesis of vitamin D.

See what Vit D does for innate immune function here
http://jcem.endojournals.org/cgi/rapidpdf/jc.2008-1454v1
full text of this paper
NONCLASSIC ACTIONS OF VITAMIN D. Bikle D.

It's also interesting to see how Vitamin d is used throughout the digestive sytem
http://www.ncbi.nlm.nih.gov/pubmed/18777944
Vitamin D and the digestive system.

Pity isn't it that with the cost of 5000iu D3 so cheap
http://www.ajcn.org/cgi/content/full/85/3/860/F1
the average UK adult runs with less than a third the amount our bodies naturally stabilise at given ample sunlight.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17218096
See how those stores fill up when your levels rise over 125nmol/l 50ng.

Sven said...

A study on an apoC-III-mutation which correlates with lower trigs, lower ldl and lower, higher hdl and less atherosclerosis.

http://www.ncbi.nlm.nih.gov/pubmed/19074352

Peter said...

Hi Sven,

Interesting paper. No suggestion in the abstract of effects on insulin sensitivity. I'd be curious to know, insulin being the driver to produce calcium deposition in the media...

Peter

nonegiven said...

http://www.ncbi.nlm.nih.gov/pubmed/19074352
Could this explain why both my triglycerides and total cholesterol were still less than 140 and LDL less than 60 even when i was diagnosed with diabetes with a fasting blood sugar of 341? As far as I know there are no Amish among my ancestors, though, there is some German and Dutch.

Also, cholesterol being required to manufacture vitamin D might explain why I have always sunburned easily instead of tanning.