Sterols are classified as steroids with 8 to 10 carbon atoms in the side chain at carbon 17 and a hydroxyl group at carbon 3. Cholesterol is the primary sterol in animal tissues, which is produced through de novo synthesis and absorption of dietary cholesterol. The Niemann-Pick C1-like 1 protein mediates the intestinal uptake of cholesterol, and the drug ezetimibe targets this protein to reduce the absorption of dietary cholesterol. Plant sterols, such as β-sitosterol, are not well absorbed by humans, with only 5% being absorbed compared to 40% for cholesterol. They are actively transported back into the intestinal lumen after entering the enterocytes. Defects in the efflux transporter ABCG5/8 lead to sitosterolemia. Plant sterols reduce the absorption of dietary cholesterol and can be ingested daily through spreads to lower plasma cholesterol levels.

Cholesteryl esters are the predominant form of plasma cholesterol and are in an esterified form with a fatty acid attached at carbon 3. This makes them even more hydrophobic than free cholesterol. Cholesteryl esters are not found in membranes and are typically present in low levels in most cells. Due to their hydrophobic nature, cholesterol and its esters need to be transported with proteins as a part of a lipoprotein particle or solubilized by phospholipids and bile salts in the bile.

Cholesterol synthesis occurs in virtually all tissues in humans, with the liver, intestine, adrenal cortex, and reproductive tissues making the largest contributions to the cholesterol pool. Acetyl coenzyme A (CoA) provides all the carbon atoms for cholesterol synthesis, while nicotinamide adenine dinucleotide phosphate (NADPH) supplies the reducing equivalents. The pathway is driven by hydrolysis of the high-energy thioester bond of acetyl CoA and the terminal phosphate bond of ATP. Enzymes in the cytosol, smooth endoplasmic reticulum (SER) membrane, and peroxisome are required for cholesterol synthesis. Regulatory mechanisms exist to balance the rate of cholesterol synthesis with the rate of cholesterol excretion. Imbalances in this regulation can lead to elevated levels of circulating plasma cholesterol, increasing the risk of vascular disease.

The first two reactions in the cholesterol biosynthetic pathway are similar to those in the pathway for producing ketone bodies. They result in the production of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). Acetyl CoA molecules condense to form acetoacetyl CoA, which is then combined with another molecule of acetyl CoA by HMG CoA synthase to produce HMG CoA. Liver parenchymal cells contain two isoenzymes of the synthase, with the cytosolic enzyme participating in cholesterol synthesis and the mitochondrial enzyme functioning in the pathway for ketone body synthesis. Mevalonate synthesis follows the production of HMG CoA.
Steroids with 8 to 10 carbon atoms in the side chain at carbon 17 and a hydroxyl group at carbon 3 are classified as sterols. Cholesterol is the major sterol in animal tissues. It arises from de novo synthesis and absorption of dietary cholesterol. Intestinal uptake of cholesterol is mediated by the Niemann-Pick C1-like 1 protein, the target of the drug ezetimibe that reduces absorption of dietary cholesterol (see p. 176). [Note: Plant sterols (phytosterols), such as β-sitosterol, are poorly absorbed by humans (5% absorbed as compared to 40% for cholesterol). After entering the enterocytes, they are actively transported back into the intestinal lumen. Defects in the efflux transporter (ABCG5/8) result in the rare condition of sitosterolemia. Because some cholesterol is transported back as well, plant sterols reduce the absorption of dietary cholesterol. Daily ingestion of plant sterol esters supplied, for example, in spreads, is one of a number of dietary strategies to reduce plasma cholesterol levels (see p. 363).]
B. Cholesteryl esters
Most plasma cholesterol is in an esterified form (with a fatty acid [FA] attached at carbon 3, as shown in Fig. 18.2), which makes the structure even more hydrophobic than free (nonesterified) cholesterol. Cholesteryl esters are not found in membranes and are normally present only in low levels in most cells. Because of their hydrophobicity, cholesterol and its esters must be transported in association with protein as a component of a lipoprotein particle (see p. 227) or be solubilized by phospholipids and bile salts in the bile (see p. 226).
III. CHOLESTEROL SYNTHESIS
Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest contributions to the cholesterol pool. As with FA, all the carbon atoms in cholesterol are provided by acetyl coenzyme A (CoA), and nicotinamide adenine dinucleotide phosphate (NADPH) provides the reducing equivalents. The pathway is endergonic, being driven by hydrolysis of the high-energy thioester bond of acetyl CoA and the terminal phosphate bond of ATP. Synthesis requires enzymes in the cytosol, the membrane of the smooth endoplasmic reticulum (SER), and the peroxisome. The pathway is responsive to changes in cholesterol concentration, and regulatory mechanisms exist to balance the rate of cholesterol synthesis against the rate of cholesterol excretion. An imbalance in this regulation can lead to an elevation in circulating levels of plasma cholesterol, with the potential for vascular disease.
A. 3-Hydroxy-3-methylglutaryl coenzyme A synthesis
The first two reactions in the cholesterol biosynthetic pathway are similar to those in the pathway that produces ketone bodies (see Fig. 16.22, p. 196). They result in the production of 3-hydroxy-3-methylglutaryl CoA ([HMG CoA], Fig. 18.3). First, two acetyl CoA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added by HMG CoA synthase, producing HMG CoA, a six-carbon compound. [Note: Liver parenchymal cells contain two isoenzymes of the synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme functions in the pathway for ketone body synthesis.]
B. Mevalonate synthesis