Cholesterol

 

 

The best known and most abundant steroid in the body is cholesterol. Cholesterol is formed in brain tissue, nerve tissue, and the blood stream. It is the major compound found in gallstones and bile salts. Cholesterol also contributes to the formation of deposits on the inner walls of blood vessels. These deposits harden and obstruct the flow of blood. This condition, known as atherosclerosis, results in various heart diseases, strokes, and high blood pressure.

Much research is currently underway to determine if a correlation exists between cholesterol levels in the blood and diet. Not only does cholesterol come from the diet, but cholesterol is synthesized in the body from carbohydrates and proteins as well as fat. Therefore, the elimination of cholesterol rich foods from the diet does not necessarily lower blood cholesterol levels. Some studies have found that if certain unsaturated fats and oils are substituted for saturated fats, the blood cholesterol level decreases. The research is incomplete on this problem.

Biosynthesis of Cholesterol

 

Slightly less than half of the cholesterol in the body derives from biosynthesis de novo. Biosynthesis in the liver accounts for approximately 10%, and in the intestines approximately 15%, of the amount produced each day. Cholesterol synthesis occurs in the cytoplasm and microsomes (ER) from the two-carbon acetate group of acetyl-CoA.

The acetyl-CoA utilized for cholesterol biosynthesis is derived from an oxidation reaction (e.g., fatty acids or pyruvate) in the mitochondria and is transported to the cytoplasm by the same process as that described for fatty acid synthesis (see the Figure below). Acetyl-CoA can also be synthesized from cytosolic acetate derived from cytoplasmic oxidation of ethanol which is initiated by cytoplasmic alcohol dehydrogenase (ADH3). All the reduction reactions of cholesterol biosynthesis use NADPH as a cofactor. The isoprenoid intermediates of cholesterol biosynthesis can be diverted to other synthesis reactions, such as those for dolichol (used in the synthesis of N-linked glycoproteins, coenzyme Q (of the oxidative phosphorylation pathway) or the side chain of heme-a. Additionally, these intermediates are used in the lipid modification of some proteins.

The process of cholesterol synthesis has five major steps:

1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)

2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of CO₂

4. IPP is converted to squalene

5. Squalene is converted to cholesterol.

5. Squalene is converted to cholesterol.

 

Pathway of cholesterol biosynthesis. Synthesis begins with the transport of acetyl-CoA from the mitochondrion to the cytosol. The rate limiting step occurs at the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation reactions are required to solubilize the isoprenoid intermediates in the pathway. Intermediates in the pathway are used for the synthesis of prenylated proteins, dolichol, coenzyme Q and the side chain of heme a. The abbreviation "PP" (e.g. isopentenyl-PP) stands for pyrophosphate. Place mouse over intermediate names to see structure.

Acetyl-CoA units are converted to mevalonate by a series of reactions that begins with the formation of HMG-CoA. Unlike the HMG-CoA formed during ketone body synthesis in the mitochondria, this form is synthesized in the cytoplasm. However, the pathway and the necessary enzymes are similar to those in the mitochondria. Two moles of acetyl-CoA are condensed in a reversal of the thiolase reaction, forming acetoacetyl-CoA. The cytoplasmic thiolase enzyme involved in cholesterol biosynthesis is acetoacetyl-CoA thiolase encoded by the ACAT2 gene. Although the bulk of acetoacetyl-CoA is derived via this process, it is possible for some acetoacetate, generated during ketogenesis, to diffuse out of the mitochondria and be converted to acetoacetyl-CoA in the cytosol via the action of acetoacetyl-CoA synthetase (AACS). Acetoacetyl-CoA and a third mole of acetyl-CoA are converted to HMG-CoA by the action of HMG-CoA synthase.

HMG-CoA is converted to mevalonate by HMG-CoA reductase, HMGR (this enzyme is bound in the endoplasmic reticulum, ER). HMGR absolutely requires NADPH as a cofactor and two moles of NADPH are consumed during the conversion of HMG-CoA to mevalonate. The reaction catalyzed by HMGR is the rate limiting step of cholesterol biosynthesis, and this enzyme is subject to complex regulatory controls as discussed below.

Mevalonate is then activated by two successive phosphorylations (catalyzed by mevalonate kinase, and phosphomevalonate kinase), yielding 5-pyrophosphomevalonate. In humans, mevalonate kinase resides in the cytosol indicating that not all the reactions of cholesterol synthesis are catalyzed by membrane-associated enzymes as originally described. After phosphorylation, an ATP-dependent decarboxylation yields isopentenyl pyrophosphate, IPP, an activated isoprenoid molecule. Isopentenyl pyrophosphate is in equilibrium with its isomer, dimethylallyl pyrophosphate, DMPP. One molecule of IPP condenses with one molecule of DMPP to generate geranyl pyrophosphate, GPP. GPP further condenses with another IPP molecule to yield farnesyl pyrophosphate, FPP. Finally, the NADPH-requiring enzyme, squalene synthase catalyzes the head-to-tail condensation of two molecules of FPP, yielding squalene. Like HMGR, squalene synthase is tightly associated with the ER. Squalene undergoes a two step cyclization to yield lanosterol. The first reaction is catalyzed by squalene monooxygenase. This enzyme uses NADPH as a cofactor to introduce molecular oxygen as an epoxide at the 2,3 position of squalene. Through a series of 19 additional reactions, lanosterol is converted to cholesterol.

The terminal reaction in cholesterol biosynthesis is catalyzed by the enzyme 7-dehydrocholesterol reductase encoded by the DHCR7 gene. Functional DHCR7 protein is a 55.5 kDa NADPH-requiring integral membrane protein localized to the microsomal membrane. Deficiency in DHCR7 (due to gene mutations) results in the disorder called Smith-Lemli-Opitz syndrome, SLOS. SLOS is characterized by increased levels of 7-dehydrocholesterol and reduced levels (15% to 27% of normal) of cholesterol resulting in multiple developmental malformations and behavioral problems.

Synthesis of Steroid Hormones From Cholesterol

Cholesterol is the precursor to all steroid hormones, including:

• Glucocorticoids (blood sugar regulation)
• Mineralcorticoids (mineral balance and blood pressure regulation)
• Sex Hormones (many functions)

Cholesterol is the precursor to a hormone called pregnenolone, which has important functions itself, but is also the precursor to all other steroid hormones.

Pregnenolone is converted to progesterone, a sex hormone, which in turn is converted into cortisol, which regulates inflammation and blood sugar, aldosterone, which regulates mineral balance and blood pressure, or testosterone, a type of sex hormone referred to as an androgen, which regulates libido, muscle mass, and plays other roles.

In females, and to a lesser degree in males, testosterone is further modified, undergoing conversion to estradiol, a different type of sex hormone called an estrogen.