2. CHOLESTEROL AND STEROIDS

4. Sterols (steroids) are class of lipids that are derivatives of a tetracyclic hydrocarbon

5. Steroids Steroids are lipids containing a steroid nucleus (core structure) The steroid nucleus is a fused ring system consisting of three cyclohexane rings and one cyclopentane ring The rings are designated A, B, C and D Attachment of different groups to the core steroid structure leads to a wide variety of steroid compounds, including cholesterol, bile salts and steroid hormones

7. CHOLESTEROL “Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal.” 6

8. Cholesterol Cholesterol is the most abundant steroid in animals - plants have very small amounts (but have related compounds) - it’s a major component of cell membranes, and affects the fluidity of the membrane due to its bulky structure - is a precursor for biosynthesis of many other steroids Cholesterol is called a sterol because it contains an alcohol group We can obtain cholesterol from our diet (animal products), but our liver can also synthesize all the cholesterol that we need - the liver synthesizes more cholesterol when dietary intake is low - excessive blood cholesterol is associated with atherosclerosis and formation of gallstones

9. History 1855 – Addison’s disease 1856 – Adrenal glands essential for life 1930 – Cortex > medulla 1932 – Cushing’s syndrome 1949 – Hench et al (Steroids in rheumatoid arthritis) 1952 – Aldosterone

10. 9 CHOLESTEROL IS THE BIOSYNTHETIC SOURCE OF ALL STEROIDS

11. Steroid Hormones Hormones act as chemical messengers They are important in control of many biological functions They are secreted from endocrine glands (and placenta) They react with receptors on cell surfaces to trigger a cascade response Usually control metabolism at the gene level Steroid hormones are biosynthesized from cholesterol

13. Adrenal Corticosteroids Adrenal corticosteroids are hormones produced in the adrenal glands (located just above the kidneys) Cortisone (a glucocorticoid) raises the blood glucose level by causing tissues other than the brain to switch to metabolizing fats and proteins; it also suppresses the immune response and can be used as an anti-inflammatory anti-allergy medication Aldosterone (a mineralcorticoid) regulates ion balance by promoting re-absorbtion of Na +, Cl - and HCO 3 - by the kidneys Prednisone is a synthetic corticoid used to treat various inflammatory conditions, such as asthma and rheumatoid arthritis

14. CHOLESTEROL IS THE BIOSYNTHETIC SOURCE OF ALL STEROID HORMONES Five major classes of hormones – Progestins (regulate events during pregnancy and are precursors to all other steroid hormones) – Androgens (male sexual characteristic development and maintenance) – Estrogens (female sexual characteristics development and maintenance) – Glucocorticoids (promote gluconeogenesis, and in certain doses suppress inflammation rxns) – Mineralocorticoids (regulate ion balance in kidney)

16. Actions… 1 Direct (Intended) Actions Anti-inflammatory Anti-allergy Anti-immunity Permissive Actions Lipolytic effects Effect on BP Effect on bronchial muscles

17. Actions …2 Glucocorticoids (e.g., prednisolone) used to suppress inflammation, allergy and immune responses. Anti-inflammatory therapy is used in many illnesses (e.g., Rheumatoid Arthritis, Ulcerative Colitis, Bronchial Asthma, eye and skin inflammations). -Useful in, say, tissue transplantation and lymphopoiesis (leukemias and lymphomas). Striking improvements can be obtained, but severe adverse, but highly predictable, effects ensue.

18. Glucocorticoids (e.g., prednisolone) used to suppress inflammation, allergy and immune responses. Anti-inflammatory therapy is used in many illnesses (e.g., Rheumatoid Arthritis, Ulcerative Colitis, Bronchial Asthma, eye and skin inflammations).

19. Actions.. 3 Hydrocortisone used for: orally for replacement therapy, i.v. for shock and asthma, topically for eczema (ointment) and enemas (ulcerative colitis). Triamcinolone: used for severe asthma and for local joint inflammation (intra-articular inj.).

21. Actions.. 4 Betamethasone and dexamethasone: very potent, w/o salt-retaining properties; thus, very useful for high-dose therapies (e.g., cerebral edemas). Beclometasone, diproprionate, budesonide: pass membranes poorly; more active when applied topically (severe eczema for local anti- inflammatory effects) than orally; used in asthma, (aerosol).

22. Beclometasone, diproprionate, budesonide: used in asthma, (aerosol).

23. BILE ACIDS ARE CHOLESTEROL DERIVATIVES Emulsify dietary lipids Secreted from liver, stored in gall bladder, passed through bile duct into intestine Bile acids represent a major metabolic fate of cholesterol, accounting for more than half of the 800 mg/day of cholesterol metabolized (steroid hormones represent about 50 mg of cholesterol per day) Bile acids are recycled through small intestine

24. Bile Salts Bile salts are synthesized from cholesterol in the liver - they are stored in the gall bladder and released into the upper small intestine to help break down fats and oils (like soaps) - too much accumulated cholesterol in the gall bladder can lead to gallstones; if a gallstone passes into the bile duct, severe pain results and the gallbladder often has to be removed

25. Bile acids 24 CholesterolCholesterol Primary bile acid Secondary bile acids Cholic acid Chenodeoxycholic acid Deoxycholic acid Litocholic acid Tauro ~ Glyco ~ Tauro ~ Glyco ~ Tauro ~ Gliko ~

26. OTHER ISOPRENOID COMPOUNDS: Vitamin A, D, K, E Terpenes – generic term for all compounds biosynthesized from isoprene precursors; hence all the molecules we have discussed today are terpenes. isoprene, has the molecular formula C 5 H 8 isoprene

27. FATE OF CHOLESTEROL Cholesterol is used by cells to decrease fluidity of cell membrane Used in steroid hormone biosynthesis Used in Vit A D E K biosynthesis Cholesterol can also be exported from liver as bile acids, cholesteryl esters, or biliary cholesterol – Cholesteryl esters are transported to other other tissues to use cholesterol

28. Androgens - male sex hormones – synthesized in the testes – responsible for the development of male secondary sex characteristics

31. Negative Health Effects Acne Irritability and aggression (ROID RAGE) Elevated cholesterol levels Adolescent use may cause a premature stop in lengthening bones (Stunted growth) Mood swings (extremes)

32. Negative Effects, cont. Injecting users subject themselves to Hepatitis or HIV. Withdrawal symptoms when one stops using steroids: mood swings, fatigue, restlessness, loss of appetite, insomnia, reduced sex drive, and depression. Depression can lead to suicide. If untreated, the withdrawal symptoms could last up to a year after stopping the use.

36. Bell Ringer Answer the following question. Why would someone want to take steroids? Are athletes the only users? Why or why not.

37. Who Uses Steroids? Athletes in sports that rely on size and strength: football, baseball, and wrestling. Endurance athletes: track and swimming. Weight training or body building athletes.