The oral fat tolerance test (OFTT) challenges with a fixed dose of a fixed type of fat. It is very important that the type of fat used and the dose given remains consistent throughout a given study. It tells us completely different things to comparing the chylomicron response to oral loads of differing fat compositions. With a fixed dose of constant fat composition we are then specifically looking at the ability of an individual to use or store fat in general.
The rise in triglycerides after an OFTT is actually chylomicrons (I'll use this term from here on) and gives us an idea of how good we are are putting fat in to use or storage. If we take any standard american chap and make him eat a standardised fat load there will be a surge of chylomicrons in his bloodstream, starting at a couple of hours after eating and going on for a few more hours.
So what determines the size of the rise in chylomicrons? As Dr Volek has pointed out, a ketogenic diet for six weeks markedly reduces your chylomicron concentration after an OFTT, ie you clear the chylomicrons from your blood stream more rapidly. This should hardly be surprising. If you have been in ketosis for 6 weeks you are hardly going to be running your metabolism on sugar. Fat comes in, fat gets used. But it still has to be transported.
How do we transport bulk fat from our gut to our butt? Dietary fat (medium chain triglycerides excepted) is ALWAYS transported in bulk as chylomicrons. "Regulated" fat, for metabolic needs, is ALWAYS transported as free fatty acids. These FFAs can be attached to albumin as their transport molecule in the plasma or can be accessed directly from chylomicrons via lipoprotein lipase, at the sites on the vascular wall where FFAs are needed by the tissues. But we can never transport all of a bulk fat meal as free fatty acids. Even when we are in ketosis. In ketosis we clear our chylomicrons faster because we are using a lot of fat. But we can never get rid of them altogether.
So if apoB48 containing chylomicrons kill, then fat kills. Post prandial chylomicrons kill. Even ketogenic diets kill. Eat anything to generate chylomicronaemia above 100mg/dl and you can kiss your coronary arteries goodbye. Gulp.
But how do we actually know that chylomicrons kill? From Denmark of course. Land of the Danish Pastry.
Denmark hosts The Copenhagen Heart Study. Just take 13,981 people, measure their non-fasting chylomicrons (described as "remnants"), record the results and watch who dies of heart disease and all cause mortality (bit risky that last one, but cardiologists were so naive back in the 70s) over the next 30 odd years. If chylomicrons kill, the higher the chylomicron count after a random meal, the more people should die, especially of heart disease.
Here are the "event" and death Hazard Ratios for men. Women are similar if not worse:
Random chylomicrons after a routine Danish breakfast or lunch are going to kill you. Heart disease. ApoB48. Simple. QED. Convincing enough to a cardiologist!
Woooooaaaaah, just a minute. This is observational. What are we observing? We are observing a group of people and they looked like this when they entered the study:
Look at hypertension incidence, diabetes incidence, physical inactivity prevalence and BMI splurge. All increase across rising chylomicron quartiles! Chylomicrons even make you smoke! They don't seem to make you alcoholic, a little disappointing that last one.
And you just thought apoB48 just caused heart disease!
Does anyone recognise the metabolic syndrome in these patient characteristics? Well I think that the size of your chylomicron surge after an average Danish pastry is determined by how far in to metabolic syndrome you are. However, the authors corrected for all of these factors and STILL chylomicrons kill.
The baseline characteristics recorded were crude in the extreme. Heavy drinking is defined as more than one drink a week (drinking two or more times a week is heavy)! But the fascinating one is diabetes. The definition of diabetes is anyone self reporting themselves as such, anyone who mainlines insulin (perhaps some body-builders got accidentally included here?), sulpha drug usage or having a random post prandial glucose above 11mmol/l.
Quick repeat: Anyone randomly detected with a blood glucose over
(actually, over 198.2mg/dl) was classed as diabetic. Perhaps they missed a few diabetics in their multifactorial adjustments! But perhaps they don't think hyperglycaemia has anything to do with heart disease.
We know from Volek that if you eat a ketogenic diet your OFTT "improves". I'll just say that again. Elevated chylomicrons levels after a fat challenge reduce if you have been eating a VERY high fat diet. I think it is a reasonable extrapolation to say that a high carbohydrate diet might worsen OFTT results.
So in Denmark a high post prandial chylomicron count, which can be viewed as a surrogate marker for the metabolic syndrome, correlates positively with your risk of heart disease. The hallmark of metabolic syndrome is hyperinsulinaemia. If that hyperinsulinaemia is inadequate to maintain normoglycaemia in the face of carbohydrate consumption then HbA1c rises and other nasty hyperglycaemic stuff happens. And the bulk fat transport gets the blame. Certainly in Copenhagen and perhaps other places too!
Let's stop bashing those poor apoB48 molecules.
As on a number of other occasions, thanks to Dr Davis for pointing to both of these studies even if I completely disagree with his interpretation of what is happening in Copenhagen. Lipophobes have such strange yet fascinating ideas. But then I love Goth stuff too.