9. Synthesis of cholesterol and ketone bodies

Last updated on November 19, 2018 at 17:16

Summary

  • HMG-CoA is synthesised from acetoacetyl-CoA and acetyl-CoA, and can either be converted into cholesterol or into ketone bodies.
  • Cholesterol synthesis takes place in the cytosol, while ketone body synthesis takes place in the mitochondria
  • The liver has two forms of HMG-CoA synthase: one in the cytosol for cholesterol synthesis, and one in the mitochondria for ketone body synthesis
  • VLDL is a lipoprotein built up from cholesterol, apolipoproteins and fat, that carries fat from the liver into the blood, where it is cleaved to LDL by lipoprotein lipase. Fat in the LDL molecules is then absorbed by tissues to be used for energy, while the rest of the molecule, now called HDL, is sent back to the liver for recycling.

Cholesterol synthesis

It begins with the thiolase reaction, a reversible reaction that combines two acetyl-CoA into one acetoacetyl-CoA. Then, acetoacetyl-CoA and acetyl-CoA are combined to yield HMG-CoA. The committing step is the next one, the reduction of HMG-CoA to mevalonate by HMG-CoA reductase. It is at this committing and irreversible step that regulation happens.

Mevalonate is then phosphorylated twice to yield the two isoprenes, isopentenyl-PP and dimethylallyl-PP. These combine to geranyl-PP, then to Farnesyl-PP. Both reactions are head-to-tail condensations. Farnesyl-PP then goes together with another Farnesyl-PP to give squalene in a head-to-head condensation reaction. Squalene then undergoes many reactions to give cholesterol.

Reaction Reaction type
First reaction of prenyl transferase Head-to-tail condensation
Second reaction of prenyl transferase Head-to-tail condensation
Squalene synthase Head-to-head condensation

The ways HMG-CoA can take; either to cholesterol or to ketone bodies.

Fatty acids can attach to cholesterol to give a cholesteryl ester, which is how fatty acids are transported. This is done by the enzymes ACAT and LCAT.

Cholesterol is also a precursor for many hormones.

Lipoproteins

Lipoproteins are complexes that consist of protein called apolipoproteins, cholesterol and triacylglycerol (fat molecules). The purpose of lipoproteins is to transport fatty acids, fat and cholesterol from the liver to the tissues of your body, where they will give fatty acids to tissues that need energy. The lipoproteins then travel back to the liver so they can be re-loaded with fatty acids. A special type of lipoprotein called chylomicrons also transport fatty acids from the diet from the intestines to the liver.

Four types of lipoproteins exist. Chylomicrons, VLDL, LDL and HDL. Chylomicrons transport fatty acids and fat from the intestines to the liver. VLDL and LDL transport fat and fatty acids from the liver to other tissues, and HDL transport the lipoproteins (now without fat and fatty acids) back to the liver.

Look at the figure below. The chylomicrons are transported through the lymph to the blood to the liver. The liver will then assemble much larger lipoproteins called VLDL, very low-density lipoprotein. These VLDL molecules are excreted into the bloodstream, where they are cleaved into smaller lipoproteins by lipoprotein lipase. These molecules have slightly higher density and are therefore called LDL. LDL will mostly travel to tissues that need energy, like adipose tissue or muscles, and deposit their fat content there. After this, the lipoprotein doesn’t contain a lot of fat anymore, and are now HDL. HDL travels back to the liver to be re-filled with fat.

How fat is transported in the body. Note that extrahepatic tissues just mean tissues that are not the liver, like muscle and adipose tissue.

Ketone body synthesis

How ketone bodies are converted into each other. All three of these are ketone bodies. Note that D-β-hydroxybutyrate isn’t strictly a ketone, but is still considered a ketone body.

When the body has synthesized acetoacetate, it can use this to create the other two ketone bodies.

Ketone bodies are produced during periods of fasting, or in case of a diet low in carbohydrates. If you don’t eat carbohydrates, just fatty acids and proteins, then the blood sugar level will drop. Some amino acids (the glucogenic amino acids) can be converted into glucose to prevent the blood glucose level from dropping to zero. However, fatty acids cannot be converted into glucose. This means that if you eat a low-carb high-fat diet, the liver will be filled with energy (from the fat) but the other tissues in the body will be starving. The liver then uses the energy  and acetyl-CoA from the fat to synthesize ketone bodies. These ketone bodies can then be transported in the blood to other tissues and then be broken down into acetyl-CoA to yield energy, in the same way glucose would.

As we saw above, the fat that we eat is transported to the liver by chylomicrons. If the blood sugar level is low (because of low-carb diet or fasting), then will the liver convert this fat into ketone bodies. The ketone bodies are then released into the blood. Tissues that need energy can then take up these ketone bodies and convert them back to acetyl-CoA. Ketone bodies are only produced in the mitochondria of the liver cells.

During the breakdown of ketone bodies, D-β-hydroxybutyrate is oxidized to acetoacetate, which receives a CoA from succinyl-CoA in the β-ketoacyl-CoA transferase reaction. Acetoacetyl-CoA is then broken down into two acetyl-CoA by thiolase.

Fatty acids cannot cross the blood-brain barrier, but ketone bodies can. The brain is therefore especially dependant on ketone bodies, as they can be used both as energy and to synthesise fatty acids in the brain.

Regulation of cholesterol synthesis

The regulation of cholesterol synthesis. The most important are the hormones and AMPK. The transcriptional regulation is not pictured.

Cholesterol cannot be broken down to be used for energy. It is therefore essential that synthesis of it is tightly regulated, and regulated by the body’s availability of energy. All regulation happens on HMG-CoA reductase. The cholesterol levels in the cell can be regulated in five ways:

1. In the short-term, HMG-CoA reductase is regulated covalently by the hormones insulin and glucagon, and by AMPK. Insulin activates HMG-CoA reductase while glucagon and epinephrine inhibit it. Regulation by AMPK means that when the cell is low on ATP, cholesterol synthesis will be inhibited.

It’s important to note that the short-term regulation does not depend on the level of cholesterol in the cell, but just on the hormones currently present in the blood. The next four regulation mechanisms depend solely on the level of cholesterol.

2. The long-term regulation happens at the transcriptional level. This means that regulating the number of HMG-CoA reductase molecules present is the most important. If there are too many, transcription of new ones should slow down.

The transcriptional regulation is accomplished by a pair of proteins called SREBP and SCAP. They are both embedded in the membrane of ER. When the level of cholesterol in the cell drops, they both migrate to Golgi, where SCAP will cleave off a part of SREBP. When that happens, this small part (a regulatory domain) will enter the nucleus and work as a transcription factor to increase transcription of various enzymes, including HMG-CoA reductase.

3. Increased levels of cholesterol in the cell activates the enzymes LCAT and ACAT. These enzymes attach fatty acids to the cholesterol molecules so that they become cholesteryl esters instead.

4. Increased levels of cholesterol causes the cell to take inn less LDL by endocytosis. LDL contains a lot of cholesterol, so by taking in less LDL the cell won’t accumulate too much cholesterol.

5. Lastly, high levels of cholesterol in the cell causes the cell to remove molecules of HMG-CoA reductase by proteolysis. By reducing the number of this enzyme will the cholesterol synthesis be slowed down.


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8. Structure and biological activities of steroids

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10. Regulation and disorders of lipid metabolism

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