Part 2 - lecture 4 - Exam

Question 1

What is cholesterol’s structure?

Answer 1

17C ring structure of 4 fused rings, single OH group at C3 - unsaturated bond at C5 and 6 - 8 member branched hydrocarbon chain at C17 - methyl group at C18 and 19

Question 2

What forms are cholesterol found in?

Answer 2

Very low water solubility - must be transported by lipoproteins – about 30% free and rest is in form of cholesterol ester with long-chyain fatty acids are attached by ester bond to OH on C3

Question 3

What does the fatty acid increase on a cholesterol ester?

Answer 3

Hydrophobicity (apolarity)

Question 4

Where is cholesterol a component?

Answer 4

Plasma and intracellular membranes – especially in brain and CNS – usually in free and unesterified form

Question 5

What is cholesterol a precursor for?

Answer 5

Bile acids and bile salts –
in liver cannot catabolize to CO2 so excreted by liver in bile acid form - and various steroid hormones – progesterone, glucocorticoid, mineralcorticoid, female and male hormones – vitamin D by being found in plant steroles (ergosterol)

Question 6

Where is cholesterol obtained from?

Answer 6

Diet - delivered in chylomicrons to periphery

Synthesis from liver and some extrahepatic tissues - delivered to liver by LDL and HDL

Question 7

In what form does cholesterol leave the liver?

Answer 7

Packaged in VLDL, or secreted to bile as free cholesterol or converted to bile acids

Question 8

Where is cholesterol synthesized in the body?

Answer 8

Liver (Greatest) but also intestine, adrenal cortex and reproductive organs in CYTOSOL

Question 9

What is the source for cholesterol synthesis and what energy is needed?

Answer 9

Made from AcCoA from glucose with help from ATP and NADPH (From PPP)

Question 10

What are the sources of AcCoA for cholesterol synthesis?

Answer 10

Most come from glucose and PDH – some comes from FA beta oxidation and some from AA oxidation (Leu and Lys)

Question 11

What is the first step in cholesterol synthesis?

Answer 11

2 AcCoA condense by acetoacetylCoA thiolase to give acetoacetyl CoA

Question 12

What is the second step in cholesterol synthesis?`

Answer 12

Acetoacetyl CoA forms HMGCoA by addition of another AcCoA and HMG CoA synthase

Question 13

What is the third step and committed step in cholesterol synthesis?

Answer 13

HMG CoA + 2 NADPH –HMG CoA reductase–> mevalonate (C6)

Question 14

What is mevalonic acid a precursor for? and how?

Answer 14

Lanosterol - first steroid structure – mevalonate is decarboxylated to a C5 that condense to form lanosterol (C30)

Question 15

What is modified to give cholesterol?

Answer 15

Lanosterol utilizing ATP

Question 16

What happens when dietary cholesterol intake is low? and high?

Answer 16

If low then liver and intestine synthesis increases, and if high liver and intestine synthesis decreases

Question 17

What is the primary site for control of cholesterol synthesis?

Answer 17

The rate limiting and committed step = HMG CoA reductase producing mevalonic acid

Question 18

How does suppression of cholesterol biosynthesis by LDL occur?

Answer 18

LDL binds receptor which extracts LDL from the blood (B-100 recognition) – LDL receptor and LDL endocytosed together and become endosomes that fuse with lysosome that contain proteases and cholesterol esterase – LDL receptor separates and returns to surface – cholesterol esters hydrolyzed by esterase to give free cholesterol and long-chain FA – free cholesterol diffuses into cytoplasm to inhibit HMG CoA reductase

Question 19

How is HMG-CoA reductase regulated?

Answer 19

Insulin upregulates, glucagon inhibits – intracellular cholesterol stimulates phosphorylation to prevent activation of transcription factor that bind the regulatory element – cholesterol upregulates esterase to form cholestryl ester that inhibits LDL receptor replenishment – cholesterol reduces stability of mRNA and reg. protein – inactivated by statin

Question 20

What is the drug class that inhibits HMG CoA reductase and how?

Answer 20

Statins - by competitive inhibition by binding to substrate binding site of enzyme

Question 21

How much can cholesterol be lowered by drugs?

Answer 21

Statins - by 50%

Question 22

What are cholesterol drugs often used in conjunction with?

Answer 22

Low-cholesterol diet and cholestyramine and colestipol which are bile salt binding drugs to promote excretion of bile salts and cholesterol

Question 23

How is cholesterol eliminated in the body?

Answer 23

It cannot be catabolized to CO2 because of ring structure so instead is converted to bile acid/salt for feces excretion or free cholesterol is secreted to bile and goes to intestine for elimination

Question 24

What are bile acids and salts?

Answer 24

Cholesterol from LDL and HDL in liver is converted into bile salt to function in intestinal fat digestion –> bile acids are made in peroxisomones of hepatocytes

Question 25

What are the most abundant bile acids in humans?

Answer 25

Derivatives of cholanic acid -- cholic acid and chenodeoxycholic acid

Question 26

What is primary bile acid structure?

Answer 26

24C with 2 or 3 OH groups and side chain ending in carboxyl group that is ionized at pH 7 = acid

Question 27

What is conjugated to bile salts and why?

Answer 27

Carboxyl group is conjugated with glycine or taurine to make them more effective detergents = more amphipatic

Question 28

What are secondary bile acids?

Answer 28

Microorganisms in intestine that chemically alter bile acids to give deoxycholic acid and lithocholic acid by removing OH group

Question 29

How is cholesterol converted to bile acid?

Answer 29

Cholesterol-7-hydroxylase is an ER associated enzyme in the liver (rate limiting step) - converts to cholic acid

Question 30

What are the functions of bile acids and salts?

Answer 30

Bile acids excrete cholesterol and prevent precipitation of cholesterol out of solution in gallbladder, solubilize cholesterol in bile, emulsify triglycerides for hydrolysis by pancreatic lipase, activate pancreatic lipase and facilitate absorption of vitamins

Question 31

What is the only significant way in which cholesterol can be excreted?

Answer 31

BIle acids

Question 32

What is the pathway of bile acids and salts excretion?

Answer 32

Secreted into bile canaliculi between adjacent hepatocytes that unite with bile ductules which come together to form bile ducts where bile acids can be carried to gallbladder for storage and the duodenum where they are excreted

Question 33

How are bile acids and salts returned to the liver?

Answer 33

Enterohepatic circulation - primary conjugated bile acids (after glycine or taurine removal) are reabsorbed by active transport process from intestine (ileum) and return to liver by portal vein -- those not reabsorbed are acted on by bacteria and become secondary bile acids which are reabsorbed passively in colon and returned to liver to be secreted into gallbladder

Question 34

What can be used to increase secretion of bile acids and salts?

Answer 34

Sequestrants like dietary fiber and cholestyramine

Question 35

What solubilizes cholesterol in the bile?

Answer 35

Phospholipids like lecithin

Question 36

When do gallstones form?

Answer 36

When cholesterol is more than lecithin and bile salts so that it can precipitate

Question 37

What are some causes for bile salt deficiency and treatment options?

Answer 37

Malabsorption of bile acid from instestine, obstruction of bile tract, sever liver dysfunction, excessive feed-back for suppression of bile acid synthesis, or increased bile acid excretion -- treated administration of chenodeoxycholic acid or removal of gallballder