Posted by: Joseph Dixon | June 1, 2014

Science: Unintended Consequences; Ancel Keys, Cholesterol, and the Transition to an Obese Society; Part XVI, What is the Function of LDL and Fat?

What is the function of LDL? Fat?

In the previous chapter I reviewed how blood LDL is responsible for CHD and how statins lower blood LDL. If LDL is so detrimental to health, why does it exist? What purpose does it serve? In order to explain the role LDL plays in health, we need to step back and discuss fat, because in the end, LDL plays an important role in the transport of this important commodity throughout the body.

Fat, the body’s gasoline

The following slide shows the energy stores in a typical human. Each box represents a pool of stored energy and its approximate size (which can vary). On the right is the approximate daily kcal (2500 kcal) burned by a male. The carbohydrate stored in the body is just able to handle this daily energy need: liver glycogen (570 kcal) + muscle glycogen (2000 kcal) + blood glucose (38 kcal) = 2,608 kcal (total carbohydrate kcal available).   If you do not eat for 24 hours, theoretically all of this carbohydrate would be used up. Therefore, the body needs an additional energy depot – the fat.

Body Energy Stores

In reality, fat is used for energy during the day so that carbohydrate is not completely used up after 24 hours. For example, it is estimated that the heart, at all times, uses 95% fatty acids for it energy source. But the question remains, how do the fatty acids in the fat get to tissues like the heart? It turns out that the body has an intricate transport system that involves the lipoprotein families and the protein albumin, the jack of all trades.  And this transport system is very important, because if this system would fail for even a few minutes, the heart would run out of fuel and stop, and you would die. See the following figure.

Fatty acid Cycle

Adipose/Liver-Free Fatty Acid/VLDL cycle (for simplicity, aka “The Dixon” cycle)

Because the Dixon cycle is a cycle, it can start anywhere and end anywhere.  In the adipocyte (Fat cell), triglyceride (TAG) is broken down to free fatty acids, which then diffuse into blood and bind to albumin, the predominant protein in blood. Albumin carries (via Blood) the free fatty acids throughout the body – especially to muscle. The left over free fatty acids are taken up by liver, where they are re-synthesized into TAGs. Apolipoprotein B (ApoB) – a protein, wraps itself around (like a belt!) a triglyceride (TAG) and cholesterol lipid droplet to form Very Low Density Lipoprotein (VLDL). The liver hepatocyte secretes VLDL into the blood. VLDL permeates throughout the body and delivers fatty acids to tissues like heart, muscle, and bone marrow. An enzyme called Lipoprotein Lipase (LPL) is on the surface of the endothelium of blood vessels and “catches” the VLDL particles. Lipoprotein lipase reaches into the droplets and hydrolyzes the fatty acids off the TAG molecule. Eventually, the remaining fatty acids (in the form of TAG) in VLDL, are returned to tissues or adipose cells. In this way all of the tissues of the body have access to energy in the form of fatty acids (the body’s gasoline). In the final step about 50% of the VLDL that has been depleted of TAG are converted to Low Density Lipoprotein (LDL), which, after a half life of 3 days, is then taken up by the liver, using LDL receptors, in order to return the remaining cholesterol and other lipids to the liver.

The “Dixon cycle” can be speeded up in the following way: The more fatty acids that are released from adipose, the more fatty acids the liver needs to takes up, the more TAG is synthesized in liver, the more VLDL is secreted by liver.

Disturbances in parts of the “Dixon cycle” can be the cause of the following chronic problems:

1. Inability to mobilize fatty acids from adipose- poor exercise stamina because glucose is utilized too fast – normally fatty acids are used for low intensity exercise.

2. In obesity, too many fatty acids are released from adipose – more than can be used – and excess fatty acids need to be sucked up by the liver, which tries to quickly repackage them into TAGs and secrete them as VLDL. If the liver gets overwhelmed by excess TAG, a fatty liver develops.

3. Hypertriglyceridemia occurs when susceptible people eat very high carbohydrate diets – excess glucose is converted to fat in liver and increased synthesis of TAG causes increased VLDL secretion – the result is hypertriglyceridemia!

4. Lipoprotein Lipase deficiency – a person with this deficiency cannot even eat a moderate fat meal because blood triglycerides can reach enormous levels – into the 1000s mg/dL.

5. Abnormal body shape – fat in the wrong places, etc. – If lipoprotein lipase is in greater amounts in different areas of the body – fat is stored in these locations (see figure). This explains the different distributions of fat between men and women.  Depending upon the precise distribution of body fat, this may lead to an unhealthy metabolic situation, as what often occurs in men.  No matter what, most people I know are not happy with their their body shape! Now they know they should blame lipoprotein lipase!

6. Chronic overproduction of VLDL leads to increased production of LDL in blood if LDL receptor amount is low!!!  This condition leads to Combined Hyperlipidemia, the most common hyperlipidemia in humans.

Fatty Acid Cycling Male vs Female

Figure caption:  “Key sex differences in adipose tissue. Compared to men, women are characterized by increased amounts of brown adipose tissue BAT and enlarged peripheral fat depots, whereas intra-abdominal fat depots are preferentially increased in men. Sex differences in the metabolic and endocrine function of these depots are associated with diminished disease risk in women. FFA free fatty acids.”

KalypsoKarastergiou, Steven R Smith, Andrew S Greenberg and Susan K Fried. Sex differences in human adipose tissues – the biology of pear shape. Karastergiouet al. Biology of Sex Differences 2012, 3:13.


Fat is the body’s gasoline and must be available every second of every day.  Therefore, multi-tissue organisms have developed lipoproteins to transport lipids through the aqueous blood. Free fatty acids are released into the blood in excess and carried throughout the body on the protein, albumin.  Excess fatty acids are taken up by the liver, repackaged into triacylglycerol molecules (TAG), and send back through the body and returned to the adipose on VLDL particles. About half of the VLDL particles are converted to LDL, which is involved in returning spent VLDL particles back to the liver. LDL also delivers cholesterol to certain tissues that need a great deal of cholesterol, such as the adrenal glands, and tissues that are rapidly growing.   So the problems that humans encounter later in life with high LDL cholesterol in the blood are the result of disturbances in the complex fatty acid distribution system that is required to keep humans alive during the course of the day and any time that excess fat stores are needed as in during exercise or during starvation. Of course, we now have statins to help when LDL cholesterol is increased in the blood.  Additionally, pharmaceuticals are being developed to manipulate PCSK9 so that LDL cholesterol concentrations can be driven even lower!

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