Friday, April 30, 2010

It’s ExASPerating!

To some in the low carb world, Acylation Stimulating Protein (ASP) is like the proverbial Gothic era crazy relative locked away in the never-to-be-entered part of the manor. They either try to forget about it or, if confronted with evidence of its existence, attempt to explain it away. ASP complicates the carbohydrate hypothesis of weight gain because it provides a mechanism whereby dietary fat can be stored without an increase in insulin. Briefly, fat cells produce ASP when they are exposed to chylomicrons (intestinally-derived packages of dietary fat). ASP up-regulates the enzyme diacylglycerol acyltransferase (DGAT) which catalyzes the final and committed step in triglyceride synthesis. Triglycerides are made from fatty acids liberated from chylomicrons by the enzyme lipoprotein lipase (LPL). ASP-directed triglyceride synthesis leads indirectly to an increase in LPL activity because increased triglyceride synthesis relieves product (i.e. fatty acid) inhibition of LPL. More LPL activity means more fatty acids will be available for triglyceride storage. ASP also inhibits the enzyme hormone sensitive lipase (HSL) resulting in decreased fat cell lipolysis, and it stimulates glucose uptake by fat cells which provides substrate for the glycerol backbone needed for triglyceride formation. All in all, it’s fairly straightforward and logical – you eat fat; your digestive system packages it into chylomicrons; the chylomicrons are transported via your blood circulation to your fat tissue; ASP is generated; ASP stimulates various biochemical mechanisms that allow you to store some amount of the fat for future use. It’s quite exquisite actually.

Individuals who don’t seem to want to give ASP a fair shake usually base their objections on two arguments:

  • 1) - Chylomicrons, which stimulate ASP production, are only in the circulation for a relatively short period of time (usually less than ½ hour) so not much fat storage will take place.
  • 2) - ASP levels don’t increase in the blood after study subjects consume fat so the in vitro studies showing chylomicron-stimulated ASP production don’t reflect what actually occurs in the human body.

Although these two statements contain facts, they don’t necessarily refute the ASP hypothesis of fat storage. As a counter to statement #1, it’s important to remember that chylomicrons themselves don’t promote fattening, ASP does. So does it really matter how long chylomicrons are in contact with fat tissue? Think of it this way: a few months ago I did something that many people can unfortunately relate to – I burned my hand while attempting to take something out of the oven. My hand was in contact with the hot surface for a fraction of a second, but for the next 24 hours, the injured area continued to get worse. It went from a barely visually discernible area to a mottled, ugly mess. In other words, destructive processes, mediated by various biochemicals, continued to damage the skin long after the initiating event. If somehow I had been able to halt the action of those biochemicals, much of the damage to my skin would not have taken place. Chylomicrons and ASP relate in much the same way. Although chylomicrons are exposed to fat cells for a relatively short time, it’s possible that the ASP produced from this exposure can remain for a much longer time prompting storage of fat. There is not a lot of research in this area, so until there are definitive answers, it’s premature to state that "this little pathway is very, very short-term".

As for statement #2, it’s important to keep in mind that when a molecule of ASP is synthesized, it acts upon the fat cell that produced it as well as neighboring cells. It does not need to leave the tissue space and enter the bloodstream to do this, unlike insulin which is produced by the pancreas and is then released into the general circulation to be transported to its target tissues all over the body. So is it really that big of a surprise that ASP levels do not rise in the peripheral blood after fat consumption? That’s not to say that ASP never enters the general circulation; if you were to have a blood sample taken from a vein in your arm, the sample would contain some amount of ASP. However, how and when ASP enters the bloodstream is controlled at the level of the microcirculation and the intricacies of this compartment are not completely understood. When looked at in action under magnification, one may see empty capillaries next to full ones, abrupt changes in blood flow direction, and other “strange” things not seen in the larger vessels of the macrocirculation. This is because the microcirculation (aka the nutritive circulation) is mainly concerned with allowing or not allowing molecule and fluid exchange between blood and cells, not with blood transportation per se. It seems that the actions of the microcirculation depend on the needs and functions of the cells close by as it has been shown that the microcirculation behaves differently in different tissues at different times. In my opinion, it is probable that ASP can be retained in the adipose tissue until it is no longer needed before being permitted to makes its way into the general circulation.  How long ASP "hangs out" in adipose tissue most likely varies according to an individual's unique metabolic state.  This could very well explain why ASP levels don’t rise in peripheral blood in a predictable manner after fat ingestion.  Of course, more research is needed to figure this all out.

In vitro experiments have shown that ASP levels rise to up to 150 times basal levels when fat cells are exposed to chylomicrons.  In contrast, insulin causes a 2 - 3 fold increase in ASP synthesis from fat cells.  These same experiments have demonstrated that ASP is the most potent in vitro stimulant of triglyceride synthesis in intact cells yet described, even more so than insulin.  Obviously more work needs to be done, but ASP may very well turn out to be a major player in fat storage and maintenance, at least for some people.  Let's not be so willing to dismiss it because it complicates a cherished dogma.  Rarely does anything good come out of that.


Stargazey said...

Hi, LynMarie! Your post gives some good insights into the importance of ASP in a low-carb diet.

I looked at the Jimmy Moore interview here.

One question that occurs to me is, how does Dr. Pogozelski know that chylomicrons last only 30 minutes in circulation? My understanding was that they were present for hours. My other question is like yours: because ASP is produced by and works directly on the fat cells, how does the blood concentration of ASP have any relationship to the activity of ASP on the adipocyte?

Although low-carb eating helps overcome insulin resistance and what Gary Taubes calls "internal starvation," it is not magic. After a certain number of calories, the metabolic advantages of ketosis and thermogenesis will be exceeded and net weight gain will result. The secretion of insulin in response to protein may explain part of it, and ASP may explain part of it, but the bottom line is that even at zero carb, it is possible to gain weight if you eat enough calories.

Stargazey said...

Here is an article measuring chylomicrons, chylomicron remannts and VLDLs following an oral fat tolerance test. There were still chylomicrons present at 8 hours after the fat meal.

LynMarie Daye said...

Thanks for bringing this to my attention, Stargazey. I'll have to find the exact papers, but I think it's been shown that when chylomicrons are injected intravenously, they only stay in the circulation for about 30 minutes (for some reason 28 minutes comes to mind as the exact number). I think these experiments are the reason people (including myself) think chylos are short-lived. But the study you posted blows that belief out of the water, doesn't it? You know, when I first heard that chylos don't remain in the circulation very long from the "anti-ASP" folks, I did some apparently not-so-thorough research, found those few papers, and said to myself "yep, they're right - chylos are short-lived." It never occurred to me that intravenously administered chylomicrons may not behave the same as chylomicrons formed in the intestines from dietary fat. My bad!

LynMarie Daye said...

I found one of the papers I remember looking at: Disposal of Human Chylomicrons Administered Intravenously in Ischemic Heart Disease and Essential Hyperlipemia

I think in a way I was a victim of confirmation bias. The notion that chylos don't last very long in the blood came from a couple of educated, respected bloggers. I assumed they were correct, so when I did my cursory search, I found this article and I guess that was enough proof for me. Reading it now, I see some things that should have caused me to dig deeper. First of all, I'm not even sure what "disappearance of chylomicron radioactivity" means. Is it the same as the disappearance of chylomicrons themselves? I think so, but I'm honestly not sure. Also, the researchers put a lot of emphasis on the "half time" disappearances, but not on when the chylos were completely cleared from the blood. And as I pointed out in my previous reply, they used infusions of chylomicrons, not an oral fat load.

Thank you for pointing this out, Stargazey. You have expanded my knowledge!

Stargazey said...

You're welcome, LynMarie! All I could remember was what I learned in basic biochemistry, and I was afraid that I had misremembered it. But it makes sense that chylomicrons are made for hours after the ingestion of a fat meal. Also, I don't know if chylomicron remants behave the same as actual chylomicrons. But in any case, the article I cited was able to measure chylomicrons and chylomicron remnants separately, and actual chylomicrons were present for a long time.

Anonymous said...

i don't have an academic background in biochemistry, somy question is somewhat simplistic and a down-to-earth:
considering that all three macronutrients can cause lipogenesis by themselves (be converted into fat), would it be strategically better not to eat both of them in a single meal (considering one is practicing intermittent fasting): i'm asking your practical advice on an approximate food combination technique: as far as i can understand is that it would be better to have only two of them (as far as it is possible) in a single meal: fat-carbs; carbs-protein; fat-protein?