1. Cholesterol and Steroid Metabolism

2. Cholesterol Definition Roles of Cholesterol Sources of cholesterol
Cholesterol synthesis & degradation

3. Cholesterol is the most common animal sterol
Definition
Cholesterol is the most common animal sterol
A fat-like substance, found in animal products and also made in the liver.

4. Roles of Cholesterol Membrane component Steroid synthesis
Bile acid/salt precursor
Vitamin D precursor

5. Sources of Cholesterol
Cholesterol synthesized
in extrahepatic tissues
De novo synthesis
Diet
Liver cholesterol
pool
Secretion of HDL
and VLDL
Free cholesterol
In bile
Conversion to bile salts/acids

6. Cholesterol Structure

7. Two main sources of cholesterol:
Dietary cholesterol
comes from the foods ( eggs, meat, fish, dairy products, and butter and in foods that contain animal products like cake, cookies and muffins).
Fruits, vegetables, and grains do not contain cholesterol.
Blood cholesterol
Found in the blood & it comes from both the cholesterol made by liver and the cholesterol and fat from diet.

8. 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 body's cholesterol pool.
Similar to ketogenic pathway
Occurs in cytosol
Requires NADPH and ATP (The pathway is endergonic, being driven by hydrolysis of the high-energy thioester bond of acetyl coenzyme A and the terminal phosphate bond of ATP.

9. 80 % in liver, ~10% intestine, ~5% skin
Highly regulated
(responsive to changes in cholesterol concentration, and regulatory mechanisms exist to balance the rate of cholesterol synthesis within the body against the rate of cholesterol excretion).
80 % in liver, ~10% intestine, ~5% skin
The vast majority of cholesterol is produced in the liver, with quite a bit being produced in the intestines.
In addition to these two sources, a number of cells
make a small amount of cholesterol for localized use in the body.

10. 1. 3-hydroxy-3-methylglutaryl (HMG) CoA
The first two reactions in the cholesterol synthetic pathway are similar to those in the pathway that produces ketone bodies. They result in the production of HMG CoA.
First, two acetyl CoA molecules condense to form acetoacetyl CoA. Next, a third molecule of acetyl CoA is added, producing HMG CoA, a six-carbon compound.
2. Synthesis of mevalonic acid (mevalonate)
The next step, the reduction of HMG CoA to mevalonic acid, is catalyzed by HMG CoA reductase. and is the rate-limiting and key regulated step in cholesterol synthesis. It occurs in the cytosol, uses two molecules of NADPH as the reducing agent, and releases CoA, making the reaction irreversible.

13. Regulation of cholesterol synthesis
HMG CoA reductase, the rate-limiting enzyme, is the major control point for cholesterol biosynthesis, and is subject to different kinds of metabolic control:

14. Sterol-dependent regulation of gene expression:
Expression of the HMG CoA reductase gene is controlled by
the transcription factor, SREBP (sterol regulatory element–
binding protein) that binds DNA at the cis-acting sterol
regulatory element (SRE) of the reductase gene. SREBP is an
integral protein of the ER membrane
2. Sterol-accelerated enzyme degradation:
The reductase itself is an integral protein of the ER membrane. When sterol levels in the cell are high, the reductase binds to specific proteins. This binding leads to ubiquitination and proteasomal degradation of the reductase.

15. 3. Sterol-independent phosphorylation /dephosphorylation:
HMG CoA reductase activity is controlled covalently through the actions of AMP–activated protein kinase (AMPK), and a phosphatase
Hormonal regulation:
The amount (and, therefore, the activity) of HMG CoA
reductase is controlled hormonally. An increase in insulin
favors up-regulation of the expression of the HMG CoA
reductase gene. Glucagon has the opposite effect.

16. HMG CoA reductase - Phosphorylation
HMG CoA reductase – OH
(active)
HMG CoA reductase – P
(inactive)
AMP-Activated
Protein Kinase (high activity)
(+)
AMP
phosphatase
kinase
(+)
(+)
AMP-Activated
Protein Kinase
(low activity)
increase cAMP
insulin
Glucagon/epi

17. Inhibition by drugs:
The statin drugs (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin) are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase (They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.

18. Lowering Cholesterol
Statins – decrease HMG CoA reductase activity

19. Elimination of Cholesterol / Conversion into bile acid derivatives
After secretion of the primary bile salts into the intestine, they may be deconjugated and dehydroxylated by the bacterial flora, forming secondary bile salts.
Dehydroxylation occurs at position 7, forming the deoxy family of bile salts.

21. Steroid Hormones
Cholesterol is the precursor of all classes of steroid hormones:
1. glucocorticoids (for example, cortisol),
2. mineralocorticoids (for example,
aldosterone), and
3. sex hormones—androgens, estrogens,
and progestins

22. Glucocorticoids and mineralocorticoids are collectively called corticosteroids
Synthesis and secretion occur in the adrenal cortex (cortisol, aldosterone, and androgens),
ovaries and placenta (estrogens and progestins), and
Testes (testosterone).
Steroid hormones are transported by the blood from their sites of synthesis to their target organs.

23. Synthesis of steroid hormones
Synthesis involves shortening the hydrocarbon chain of cholesterol, and hydroxylation of the steroid nucleus.
The initial and rate-limiting reaction converts cholesterol to the 21-carbon pregnenolone.
NADPH and molecular oxygen are required for the reaction.
Pregnenolone is the parent compound for all steroid hormones.
Pregnenolone is oxidized, then isomerized to progesterone, which is further modified to the other steroid hormones (such as testosterone, cortisol, aldosterone) by hydroxylation reactions.

24. Secretion of adrenal cortical steroid hormones
Steroid hormones are secreted on demand from their tissues of origin in response to hormonal signals.
Corticosteroids and androgens are made in different regions of the adrenal cortex, and are secreted into blood in response to different signals.

25. 1. Cortisol
It is secreted by the middle layer of the adrenal cortex.
The secretion is controlled by the hypothalamus, to which the pituitary gland is attached.
Cortisol allows the body to respond to stress through its effects on intermediary metabolism and the inflammatory response.

26. 2. Aldosterone
A hormone produced by the outer-section of the adrenal cortex in the adrenal gland.
Acts in the kidney to cause the conservation of sodium, secretion of potassium, increased water retention, and increased blood pressure.
It’s overall effect is increasing ions- and water- reabsorption in the kidney.

27. 3. Androgens
Stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the activity of the accessory male sex organs and development of male secondary sex characteristics.
Androgens are also the original anabolic steroids and the precursor of all estrogens, the female sex hormones. The primary and most well-known androgen is testosterone.

28. Degradation of steroid hormones
Steroid hormones are generally converted into inactive metabolic excretion products in the liver.
Reactions include reduction of unsaturated bonds and the introduction of additional hydroxyl groups.
The resulting structures are made more soluble by conjugation with glucuronic acid or sulfate.
Approximately 20–30% of these metabolites are secreted into the bile and then excreted in the feces,
whereas the remainder are released into the blood and filtered from the plasma in the kidney, passing into the urine. These conjugated metabolites are fairly water-soluble and do not need protein carriers.