6.3 Lipid Metabolism

6.3 Lipid Metabolism Pathways

Five lipid metabolic pathways/processes will be covered in the following subsections:

• Lipolysis (Triglyceride Breakdown)

-Breakdown of triglycerides to glycerol and free fatty acids.

• Fatty Acid Oxidation (Beta-Oxidation)

-Breakdown of fatty acids to acetyl-CoA

• De Novo Lipogenesis (Fatty Acid & Triglyceride Synthesis)

-Synthesis of fatty acids from acetyl-CoA and esterification into triglycerides

• Ketogenesis (Ketone Body Synthesis)

-Synthesis of ketone bodies from acetyl-CoA

• Cholesterol Synthesis

6.31 Lipolysis (Triglyceride Breakdown)

Lipolysis is the cleavage of triglycerides to glycerol and fatty acids, as shown below.

Figure 6.311 Lipolysis

There are two primary lipolysis enzymes:

• Lipoprotein lipase (LPL)
• Hormone-sensitive lipase (HSL)

Despite performing the same function, the enzymes are primarily active for seemingly opposite reasons. In the anabolic state, LPL on the lining of blood vessels cleaves lipoprotein triglycerides into fatty acids so that they can be taken up into adipocytes (fat cells) for storage as triglycerides, or myocytes (muscle cells) where they are primarily used for energy production.

This action of LPL on lipoproteins is shown in Figures 6.312 & 6.313.

Figure 6.312 Lipoprotein lipase cleaves fatty acids from the chylomicron, forming a chylomicron remnant.

Figure 6.313 Lipoprotein lipase cleaves triglycerides from VLDL and IDL, forming subsequent lipoproteins (IDL and LDL) that contain less triglyceride

HSL is an important enzyme in adipose tissue, which is a major storage site of triglycerides in the body. HSL activity is increased by glucagon and epinephrine (“fight or flight” hormone), and decreased by insulin. Thus, during hypoglycemia (such as during a fast; a catabolic state), or a “fight or flight” response, triglycerides in the adipocytes (fat cells) are cleaved, releasing fatty acids into circulation that then bind with the transport protein albumin that carry them to muscle cells for use as an energy source. Thus, HSL is important for mobilizing fatty acids so they can be used to produce energy. The figure below shows how fatty acids can be taken up and used by tissues such as the muscle for energy production1.

Figure 6.314 Hormone-sensitive lipase

We are not going to focus on glycerol (the other product of triglyceride breakdown), but it does have two metabolic fates.

• It can be broken down in glycolysis
• It can be used to synthesize glucose (gluconeogenesis)

Figure 6.315 Metabolic fates of glycerol

References & Links

1. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw’s Perspectives in Nutrition. New York, NY: McGraw-Hill.

De novo Lipogenesis (Fatty Acid Synthesis)

De novo in Latin means “from the beginning.” Thus, de novo lipogenesis is the synthesis of fatty acids, beginning with acetyl-CoA. You will remember that acetyl-CoA is the product of the transition reaction that is the starting point of the citric acid cycle. We had mentioned earlier

(in Section 6.25) that “Acetyl-CoA is a central point in metabolism.” Acetyl-CoA moves out of the mitochondria, where it is subsequently combined with additional acetyl-CoA molecules to form palmitate, a 16-carbon fatty acid1. The palmitate produced can be used as a component in the production of triglycerides (fat) for storage.

Figure 6.331 Fatty acid synthesis2

References

• Gropper SS, Smith JL, Groff JL. (2008) Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing.
• http://en.wikipedia.org/wiki/Mitochondrion

Ketone Body Synthesis

In cases where there is not enough glucose available for the brain (very low carbohydrate diets, starvation), the liver can use acetyl-CoA to synthesize ketone bodies (ketogenesis). The

structures of the three ketone bodies; acetone, acetoacetic acid, and beta-hydroxybutyric acid, are shown below.

Figure 6.341 The three ketone bodies, from top to bottom (acetone, acetoacetic acid, and beta- hydroxybutyric acid1)

After they are synthesized in the liver, ketone bodies are released into circulation where they can travel to the brain. The brain converts the ketone bodies to acetyl-CoA that can then enter the citric acid cycle for ATP production, as shown below.

Figure 6.342 The production, release, use, or exhalation of ketone bodies2

If there are high levels of ketones secreted, it results in a condition known as ketosis or ketoacidosis. The high level of ketones in the blood decreases the blood’s pH, meaning it becomes more acidic. It is debatable whether mild ketoacidosis (as seen with ketogenic and

Atkin’s diets) is harmful, but severe ketoacidosis can be lethal. One symptom of this condition is fruity or sweet-smelling breath, which is due to increased acetone exhalation.

References & Links

• http://en.wikipedia.org/wiki/File:Ketone_bodies.png
• http://commons.wikimedia.org/wiki/File:Liver.svg

Cholesterol Synthesis

Acetyl-CoA is also used to synthesize cholesterol. As shown below, there are a large number of reactions and enzymes involved in cholesterol synthesis. You will not have to memorize all these steps, but it does illustrate the complexity of this process.

Figure 6.351 Cholesterol synthesis pathway1

Simplifying this, acetyl-CoA is converted to acetoacetyl-CoA (4 carbons) before forming 3- hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is converted to mevalonate by the enzyme HMG-CoA reductase. This enzyme is important because it is the rate-limiting enzyme in cholesterol synthesis.

Figure 6.352 Cholesterol synthesis simplified2

A rate-limiting enzyme is like a bottleneck in a highway, as shown below, that determines the flow of traffic past it. Traffic is limited in how fast it can flow due to the emergency vehicle (rate-limiting enzyme) slowing it down.

Figure 6.353 Bottleneck in traffic3

Rate-limiting enzymes limit the rate at which a metabolic pathway proceeds. The pharmaceutical industry has taken advantage of this knowledge to lower people’s LDL (“bad” cholesterol) levels with drugs known as statins. These drugs inhibit HMG-CoA reductase and thus decrease cholesterol synthesis. Less cholesterol leads to lower LDL levels, and hopefully a lower risk of cardiovascular disease.

The brand names of some common statins approved for use in the US include: Lipitor

Lescol Crestor Zocor Livalo

The body synthesizes approximately 1 gram of cholesterol a day, whereas it is recommended that we consume less than 0.3 gram a day. A number of tissues synthesize cholesterol, with the liver accounting for ~20% of synthesis. The intestine is believed to be the most active among the other tissues that are responsible for the other 80% of cholesterol synthesis5.

References & Links

• https://en.wikipedia.org/wiki/Statin#/media/File:HMG-CoA_reductase_pathway.png
• http://en.wikipedia.org/wiki/File:Squalene.svg
• http://en.wikipedia.org/wiki/File:Bottleneck.svg
• http://www.medicinenet.com/statins/page3.htm
• Gropper SS, Smith JL, Groff JL. (2008) Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing.