In Defense of Glyceroneogenesis Researchers (not that they really need it)

A few days ago, Jimmy Moore aired an interview he did with Gary Taubes in which they discussed a myriad of topics.  Jimmy asked Gary if there was anything he would change in his book Good Calories, Bad Calories based on new information he had come across since its publication. Gary answered that he wished he hadn't stated that dietary carbohydrates were absolutely required to store fat in fat tissue because he has since learned that a process called glyceroneogenesis casts doubt on that assertion.  As someone who has written about glyceroneogenesis and low carb diets, I'm glad Taubes is spreading the word.

What I have a problem with is a comment left at Jimmy's site that comes across as biased against and dismissive of the scientists who elucidated glyceroneogenesis:

"I actually had a look again at one of the so called ‘studies’ explaining this Glyceroneogenesis process in this post:

http://adipo-insights.blogspot.com/2009/09/is-fable-of-unfettered-fat-burning.html

This study is basically flawed, even a layman like me can see things such as the fact that the test subjects were not keto-adapted and I believe that a total different set of rules apply for people who are not keto-adapted. There are some other flaws too, and I think at the end the basic biochemistry that Gary mentioned to in GCBC will carry more weight (take up a bigger part of a pie-chart of total processes) at the end."

I'm not sure what study this person is referring to since I didn't reference any study (i.e. primary research) concerning glyceroneogenesis, only two review papers, but the quotation marks around the word studies, as well as the term so called, indicates to me that this person believes that the glyceroneogenesis research to date is either worthless, corrupted, laughable, or some combination of the three.  I agree that keto-adaptation may affect the rate of glyceroneogenesis, but the fact that these researchers haven't examined that particular condition yet doesn't make their research "flawed".  These scientists are not trying to prove or disprove any low carbohydrate diet theory; they are trying to understand basic biochemistry.  And yes, glyceroneogenesis, although not well known, is a very important component of basic biochemistry because the ability to re-esterify fatty acids is critical to human metabolism.

I find it more than a bit ironic that an individual who appears to be an ardent fan of Taubes' Good Calories, Bad Calories would criticize the work of researchers who behave similarly to the "real" scientists lauded in the book.  In this article, Richard Hanson, Ph.D., one of the discoverers of the glyceroneogenic pathway, tells us how his and his colleagues' desire to answer an intriguing question, brought about by a scientific observation, led them on the journey to uncover glyceroneogenesis:

"By 1967 it had been well established that both pyruvate carboxylase and PEPCK-C were involved in hepatic and renal gluconeogenesis. So it was a real surprise that year when John Ballard and I found pyruvate carboxylase in adipose tissue, a tissue that did not make glucose. We proposed that pyruvate carboxylase played an anaplerotic role (i.e. it replenished citric acid cycle anions) during lipogenesis in adipose tissue, because citrate efflux from the mitochondria depletes intermediates of the citric acid cycle. This is similar to the function of the enzyme in the liver during gluconeogenesis. We came to the totally incorrect conclusion that there were both mitochondrial and cytosolic forms of the pyruvate carboxylase in adipose tissue. It turned out that it is easy to break mitochondria during their isolation from adipose tissue and thus release the enzyme. In the same year, John and I, together with Gilbert Leveille, reported that adipose tissue also contained PEPCK-C. What was this gluconeogenic enzyme doing in a tissue that does not make glucose?"

And the rest is scientific history.  Something tells me Gary would approve.

Some Thoughts on VLDL, Carbs, & Insulin

A reader asked me to comment on the article below.  He recognized that the author was wrong when he wrote that LDL breaks down into VLDL and was wondering about the rest of the information in the article.  I decided to make my reply a separate post since there is much to discuss here. 

Question: What is VLDL cholesterol? Can it be harmful?

Answer:
from Thomas Behrenbeck, M.D.

Very-low-density lipoprotein (VLDL) cholesterol is a type of lipoprotein. Although you may hear about VLDL, your VLDL level usually isn't reported to you as a part of a routine cholesterol test.

There are several types of cholesterol, each made up of lipoproteins and fats. Each type of lipoprotein contains a mixture of cholesterol, protein and a type of fat (triglyceride), but in varying amounts.

Of the lipoprotein types, VLDL contains the highest amount of triglyceride. Because it contains a high level of triglyceride, having a high VLDL level means you may have an increased risk of coronary artery disease (CAD), which can lead to a heart attack or stroke.

There's no simple, direct way to measure VLDL cholesterol, which is why it's normally not mentioned during a routine cholesterol screening. VLDL cholesterol is usually estimated as a percentage of your triglyceride value. A normal VLDL cholesterol level is between 5 and 40 milligrams per deciliter.

So you can see from this why eating carbohydrates causes your VLDL to rise. VLDL is made up of mostly triglycerides, which require glycerol in order to be formed. The more glycerol present in your body, the more triglycerides your body will have to create. It's interesting that this particular type of triglyceride that effects the LDL is made in the liver.

As we learned in Taubes, when we eat food, it is broken down and all the various acids go to fat tissue first before being added to the bloodstream. So in terms of glycerol, this is added to the bloodstream and once the stream reaches adipose tissue, the glycerol undergoes the esterification process for passage in and out. Esterification is the formation and breakdown of triglycerides. These triglycerides are offered to every cell, muscle and tissue in the body as they travel through the blood stream. All of us should know that we can only have a small amount of sugar in our bloodstream at any point in time -- so this idea that we use all this sugar for energy is nonsensical to say the least.

Anyway, when it makes its rounds through the bloodstream and there are no takers, it goes to the liver where it is sent out on lipoproteins. This is the beginning of breaking the LDL down into VLDL which is a bad thing. This is why you have seen me write that the body sends sugar to one of 4 places in order to get rid of it, not for some beneficial purpose. It's true that our bodies require a steady amount of blood sugar, but this sugar is not that which is derived from eating carbohydrates, regardless of how similar it is in composition. The sugar you eat goes to fat. The liver produces the small amount that we require and anything beyond that requirement either goes to fat or degrades our cholesterol. Under ZC (zero carbohydrate) circumstances, our bodies are perfectly capable of making whatever sugar we require. We are not required to have any of this from our diet.

First I have to say that it is rather suspicious to me that an M.D. would have his "facts" so messed up.  Graduating from medical school certainly doesn't mean you know everything but this is BAD!  For what it's worth, I don't believe this person is really a physician.  An individual can present themselves any way they want on the Internet, and I believe we have ourselves a poser here.

It's difficult to discuss the article point by point since honestly I can't make heads nor tails of it, so I'm simply going to discuss some thoughts I have on VLDL, diet, and coronary artery disease as a whole.  The best way to begin is to explain briefly how VLDL are formed.  Their synthesis takes place in the liver where a molecule of apolipoprotein B-100 (apo B) forms a complex with phospholipids and cholesterol encasing a core of cholesteryl esters and triglycerides.  VLDL function primarily as carriers for triglycerides and as such contain many more triglycerides than cholesteryl esters.  VLDL enter the bloodstream and travel to various tissues, most notably fat tissue and muscle, where they are acted upon by the enzyme lipoprotein lipase (LPL) which releases some of the triglycerides so that they can be stored (in fat tissue) or used for energy production (in muscle).  As they lose their triglyceride cargo, VLDL become smaller and denser and eventually end up as LDL (low density lipoproteins).  This is a very simplified description; if you would like something much more in-depth, I suggest this article: Plasma Lipoproteins: Composition, Structure, and Biochemistry.

As for carbohydrate intake causing fasting VLDL to rise, it often does but this is not necessarily a harmful occurrence.  The amount of VLDL in the blood is the result of the rate of VLDL production together with the rate of VLDL clearance.  It is generally thought that an elevated VLDL level caused by increased production is harmful (or at least associated with harm) while an elevated VLDL level caused by decreased clearance is not.  It all comes down to insulin resistance.

It's often stated that insulin drives VLDL synthesis by the liver; this is a very misleading statement.  Believe it or not, insulin acutely inhibits liver VLDL production, particularly the large triglyceride-rich "bad" VLDL1.  This makes sense because after eating, triglycerides in chylomicrons would be competing for clearance with triglycerides in VLDL.  By slowing down production of VLDL, chylomicrons can be cleared from the circulation more efficiently.  Insulin slows down VLDL synthesis in several ways, the most obvious being via inhibition of fat cell lipolysis so that less fatty acids are delivered to the liver for triglyceride synthesis.  Insulin also exerts several direct effects on the liver itself such as increasing the degradation of apo B.  If an individual's fat cells (some experts assert that visceral fat cells are more important in this regard) and liver are resistant to the actions of insulin, it's easy to see why they would have an elevated VLDL concentration.  It's also interesting to speculate if elevated VLDL triglycerides may merely be a marker for insulin resistance and not harmful to the coronary arteries in and of themselves.  Consider people with the rare genetic condition called Fredrickson type V hyperlipidemia.  These individuals have extremely high VLDL and triglyceride concentrations due to decreased peripheral clearance caused by a deficiency of lipoprotein lipase.  Yet when their vascular endothelial function (an indication of coronary artery disease risk) was compared to subjects with normal triglyceride levels, no significant difference was found.  If VLDL triglycerides per se cause harm to the vascular endothelium, surely people with an average serum triglyceride concentration of 1914 mg/dl would exhibit some measurable degree of endothelial dysfunction over and above individuals with normal triglyceride levels.  Yet they don't appear to.  It's also important to note that Fredrickson type V hyperlipidemia does not seem to be associated with an increased risk of CAD.

Which brings us to the notion of moderately elevated VLDL being physiologically unremarkable when due to decreased peripheral clearance.  It has been shown that carbohydrate-induced hypertriglyceridemia is caused primarily by decreased clearance not increased production, assuming the person is insulin sensitive and the carbohydrates are mostly starches and not sugars.  It's been theorized that this reduction in VLDL triglyceride clearance "may reflect a homeostatically appropriate down-regulation of the LPL activity of skeletal muscle".  In other words, when one consumes a lot of carbohydrates especially without a lot fat, muscles will preferentially switch to using more glucose for fuel and therefore will not need to take up as much fat from the circulation, hence the reduction in skeletal muscle LPL activity.

How high can triglycerides go on a low sugar, high carbohydrate diet and still be considered "safe"?  In my opinion, a triglyceride concentration up to about 150 mg/dl is acceptable based on the fact that several CAD-free populations consuming their native high carbohydrate/low fat diets have such a level.  It's important to note however that the higher the carbohydrate-to-fat ratio, the higher the triglyceride concentration will generally be.  This means that a moderate amount of carbohydrates shouldn't lead to a 150 mg/dl triglyceride level if everything is working as it should.  That level of triglycerides on a moderate carbohydrate diet could indicate insulin resistance.

What this all means in the real world is this:  if an individual who has a fasting triglyceride concentration of 70 mg/dl on a standard Western diet (indicating that they are probably insulin sensitive) begins a high carb/low sugar/low fat diet (let's say 65% carbohydrate, 20% fat) and their triglyceride level elevates to 130 mg/dl, this is most likely a benign, totally appropriate change.  In this case, an elevation of triglycerides is most likely not a bad thing.