Cholesterol metabolism

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Cholesterol metabolism



Cholesterol metabolism


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USMLE® Step 1 questions

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High Yield Notes

10 pages


Cholesterol metabolism

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USMLE® Step 1 style questions USMLE

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A research study is performed to better understand the function of a molecule that leads to the stiffening of coronary arteries when found in high concentrations in rat models. An adrenal biopsy isolates the compound, with the chemical structure outlined below. Which of the following describes a critical cellular function of this molecule?  

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atherosclerosis p. 308

in bile p. 383

cholelithiasis and p. 405

functions p. 48

lipid-lowering agents p. 327

synthesis of p. 46, 71, 71, 77

vitamin B3 effects p. 65

Cholesterol desmolase p. 338

Lecithin-cholesterol acetyltransferase (LCAT)

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Cholesterol is a lipid molecule that helps maintain the structure of cell membranes, and is a precursor to steroid hormones, bile acids, and vitamin D.

As it turns out, we make most of our cholesterol ourselves, but some comes through the diet.

Cholesterol synthesis, also called the mevalonate pathway, happens in the smooth endoplasmic reticulum of a cell.

It begins with 2 acetyl-CoA molecules getting joined together by the enzyme acetyl-CoA acyl-transferase.

The result is a 4-carbon molecule called acetoacetyl-CoA and then a free CoA molecule.

Next, the enzyme HMG-CoA synthase combines acetoacetyl-CoA and acetyl-CoA to form a 6-carbon molecule called 3-hydroxy-3-methylglutaryl CoA, or HMG-CoA - so 3 acetyls and the an free CoA molecule.

Then, an enzyme called HMG-CoA reductase reduces HMG-CoA into mevalonate, by removing a CoA-SH and a water molecule.

This step with HMG-CoA reductase is the rate-limiting step of cholesterol synthesis.

In other words, the rate of this reaction determines the overall rate of cholesterol synthesis - it’s like the slowest step in the assembly line for a factory.

Now, cholesterol synthesis is regulated by a trio of proteins - sterol regulatory element binding protein - or SREBP and two others that just go by SCAP and INSIG-1.

Let’s say that cholesterol levels drop because there’s less cholesterol coming into the cell from the diet.

In that situation, INSIG-1 falls off of SREBP, like pulling a pin from a grenade, and the SREBP-SCAP complex then gets cleaved by cellular enzymes.

The cleaved SREBP floats into the nucleus, and binds to the sterol regulatory element on the DNA.

When it binds, it increases expression of the genes encoding HMG-CoA reductase.

That leads to more HMG-CoA reductase, which speeds up endogenous cholesterol synthesis.

Once HMG-CoA reductase has made the 6 carbon mevalonate, it then undergoes a number of additional enzyme-mediated transformations before it becomes cholesterol.

First, the enzyme mevalonate-5-kinase uses adenosine triphosphate, or ATP, to phosphorylate mevalonate, creating mevalonate-5-phosphate.

Then, phosphomevalonate kinase uses another ATP to phosphorylate mevalonate-5-phosphate, making mevalonate pyrophosphate.

Finally, mevalonate pyrophosphate decarboxylase removes a carboxyl group from it, forming a 5 carbon molecule called isopentenyl pyrophosphate.

Next, geranyl transferase condenses 3 of these isopentenyl pyrophosphate molecules to form a 15 carbon molecule called farnesyl pyrophosphate.


Cholesterol is a lipid molecule that helps to synthesize hormones, cell membrane integrity, and other important compounds. Cholesterol is synthesized in the smooth endoplasmic reticulum of cells throughout the body, but mainly in the liver. This reaction's rate-limiting step is the reduction of HMG CoA to mevalonate, which is done by HMG-CoA reductase.

Some of the cholesterol in the blood is derived from food. Dietary cholesterol is found in animal products, such as meat, poultry, fish, and dairy products. In the bloodstream, cholesterol is transported and attached to proteins called lipoproteins, which carry it to the cells that need it.


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