L39 – Unveiling the myth: the science of cholesterol and lipids

Question 1

Structure of cholesterol. How many rings, which ring is different in shape to the rest, what is attached to certain rings?

Answer 1

Sterol nucleus- 4 rings ABCD
D ring is 5 carbon, rest is 6 carbon
 Hydrophilic head: OH at C3
 Hydrophobic tail: long hydrocarbon chain

Question 2

Name some functional molecules formed from cholesterol ?

Answer 2

Bile salts
Steroid hormones
Vitamin D
plasma membrane

Question 3

What is glycoholic acid and what is it made of?

Answer 3

Conjugated bile salt (due to difference in pKa of bile salt and intestine causing ionization)

Made of cholic acid (sterol) and glycine

Question 4

Name of enzyme for converting cholesterol ester to free cholesterol for absorption?

Answer 4

Cholesterol esterase

Cholesterol ester + water > free cholesterol + fatty acids

Question 5

Dietary cholesterol intake influence plasma LDL cholesterol?

Answer 5

Dietary cholesterol intake increase = little influence on plasma LDL cholesterol

Question 6

In smalll intestine, what processes occur to allow absorption of dietary lipids?

Answer 6

Bile salts emulsify lipid, free cholesterol packaged into in micelle, Pancreatic enzyme degrade lipid for adsorption

Question 7

products of pancreatic lipase catalysis of TAG?

Answer 7

TAG > 2-Monoacylglycerol + fatty acids

Question 8

What are the primary products of small intestine digestion?

Answer 8

Free fatty acids
Cholesterol
2-monoacylglycerol

Question 9

What happens to primary products in intestine? What happens to free cholesterol in enterocyte?

Answer 9

Immediately reesterify
primary products for
packaging into chylomicrons

Free cholesterol convert to Cholesterol ester by ACAT2 enzyme

Question 10

In the intestinal mucosal cell, what 5 things are incorporated into a chylomicron? (exogenous)

Answer 10

Apo B-48
Phospholipids 
TAG 
Cholesterol ESTER
fat soluble vitamins

Question 11

What maintains the concentration gradient for cholesterol uptake into intestinal mucosal cell?

Answer 11

Reaction turning free cholesterol to cholesterol ester by ACAT2 enzyme
+
shuttling of CE with apo B48 to chylomicrons via MTP

Question 12

What is the channel for transporting free cholesterol into intestinal mucosal cells?

Answer 12

NPC1L1 receptor

enter through endocytosis

Question 13

Where do chylomicrons carry CE to?

Answer 13

Lymphatic system> blood > hepatocytes

Question 14

How can bile acid exit blood and be excreted?

Answer 14

From hepatocyte > blood > enterocyte > NPC1L1 receptor > intestinal lumen > excreted

Question 15

When is bile acid in the intestine lumen reabsorbed for use?

Answer 15

Recycled back into blood when dietary intake of fat happens

Question 16

Which form of cholesterol is majority in body?

Answer 16

85 - 90% Free cholesterol

10-15% CE

Question 17

How does age relate to increase dietary cholesterol absorption?

Answer 17

Increase age = increase NPC1L1 expression = increase dietary cholesterol absorption

Question 18

What can inhibit NPC1L1 to cause decrease in LDL-C in plasma?

Answer 18

by taking drug: Ezitimibe

Question 19

What microbe can modify bile acids in intestines?

Answer 19

Gut flora with Bile Acid Hydrolase

Question 20

What does gut flora help make to facilitate excretion? What does this molecule do to primary bile salts?

Answer 20

Gut flora makes secondary bile salts (modified bile acid), facilitate excretion/ less reabsorption of primary bile salt

Question 21

Consequence of overall reabsorption of bile acids to extrahepatic circulation ?

Answer 21

liver uses cholesterol to make new bile acids to maintain the pool > balance dietary cholesterol intake

Question 22

How does age affect plasma LDL levels via gut flora?

Answer 22

Increase age = decrease in BSH+ gut flora = less secondary bile acids made= less excretion/ more reabsoprtion of primary bile acids = less cholesterol used to replace bile acid = elevate plasma LDL level

Question 23

How can plasma LDL be reduced in old people with reduced BSH+ gut flora?

Answer 23

pplement with probiotic strains (e.g. eat yoghurt with BSH+) > make secondary bile acid > excrete bile acid, reabsorb less, use more cholesterol > reduce LDL-C

Question 24

What lipoprotein carries cholesterol from peripheral tissue to liver?

Answer 24

HDL

Question 25

What are the 2 sources of cholesterol inside hepatocyte?

Answer 25

From peripheral tissue delivered via HDL (or remodeled VLDL...) Cholesterol synthesis inside hepatocyte

Question 26

Which lipoprotein can linger in plasma?

Answer 26

LDL

Question 27

What carries LDL into hepatocyte?

Answer 27

LDLR | LDL receptor

Question 28

How does age change the number of LDLR on hepatocytes?Why?

Answer 28

Increase age = less LDLR Due to decreased cholesterol demand for synthesis of bile acid inside hepatocyte due to decrease in BSH+ gut flora> less excretion of bile acid

Question 29

What gene expression changes with age that is crucial for bile acid synthesis?

Answer 29

CYP7A1 expression declines with age > decrease capacity for bile acid synthesis > increase cholesterol in plasma

Question 30

Increased LDL residence time and decreased LDL clearance lead to what level of LDL in plasma?

Answer 30

High

Question 31

Number of stages in cholesterol synthesis inside hepatocyte?

Answer 31

4

Question 32

Which of the stages of cholesterol synthesis inside hepatocyte is rate-limiting?

Answer 32

Stage 1

Question 33

What does stage 1 of cholesterol synthesis inside hepatocyte involve?

Answer 33

Conversion of 3 molecules of acetyl CoA to MEVALONIC ACID

Question 34

What are the enzymes used in conversion of acetyl CoA to mevalonic acid ? Which enzyme is used in a non-reversible step?

Answer 34

HMG-CoA synthase + HMG-CoA reductase HMG-CoA reductase

Question 35

What enzyme is trageted by statins to inhibit cholesterol synthesis in hepatocyte? How does statins inhibit this enzyme?

Answer 35

HMG-CoA reductase targeted to stop cholesterol synthesis at stage 1 (cannot produce mevalonic acid Statin is a competitive inhibitor

Question 36

How do insulin and glucagon affect stage 1 of choesterol synthesis in SHORT-TERM regulation of cholesterol?

Answer 36

Insulin (fed state) promote HMG-CoA reductase > more cholesterol synthesis in hepatocyte Glucagon limit activity

Question 37

How does insulin promote HMG-CoA reductase acitivty in short-term cholesterol regulation?

Answer 37

Insulin stimulates phosphatase that dephosphorylate inactive reductase to active form

Question 38

How does glucagon limit HMG-CoA reducatase activity in short-term cholesterol regulation?

Answer 38

Stimulate AMP-activated protein kinase that phosphorylates active reductase to inactive form

Question 39

What happens in stage 2 of cholesterol synthesis in hepatocyte?

Answer 39

Formation of activated ISOPRENE UNITS from mevalonic acids Requires lots of ATP and oxygen

Question 40

What happens in stage 3 of cholesterol synthesis in hepatocyte?

Answer 40

form SQUALENE from 6 isoprene units

Question 41

What happens in stage 4 of cholesterol synthesis in hepatocyte?

Answer 41

Cyclization reaction steps convert squalene to Cholesterol

Question 42

Give the end-products of each stage of cholesterol synthesis in hepatocyte?

Answer 42

Acetyl CoA > Mevalonic acid > Isoprene units > Squalene > Cholesterol

Question 43

3 ways cholesterol synthesis is regulated?

Answer 43

Sterol-dependent regulation of gene expression Sterol- accelerated enzyme degradation Sterol- independent phosphorylation/ dephosphorylation

Question 44

What molecules upregulate expression of gene for HMG-CoA reductase?

Answer 44

Thyroxine Insulin

Question 45

How does Sterol -accelerated regulation of cholesterol synthesis work?

Answer 45

Increase in cholesterol conc. > acitvate degradation of HMG-CoA reductase at ER > less cholesterol synthesis

Question 46

How does Sterol-dependent regulation of gene expression work?

Answer 46

Decrease in cholesterol conc. > remove inhibitory effect on HMG-CoA reductase synthesis > more HMG-CoA reductase made > increase cholesterol synthesis

Question 47

What are the 2 mechanisms of cholesterol removal from liver?

Answer 47

1. Direct efflux through gallbladder to small intestine | 2. Conversion to bile acids > efflux to gallbladder

Question 48

What chemical is used for gallbladder response to release hepatic cholesterol?

Answer 48

gallbladder responses to cholecystokinin (hormone) > releases hepatic cholesterol into small intestine

Question 49

What type in Frederickson classification is familial hypercholesterolemia?

Answer 49

IIa

Question 50

Cause of Familial | hypercholesterolemia?

Answer 50

79% = mutations in LDLR gene > deficiencies > unable to take LDL back to liver > high plasma cholesterol conc. rest= caused by mutation in PCSK9 (mutant = not able to bind to LDLR and degrade receptor, less capacity for LDL absorption into liver) or apo B or ARH

Question 51

FH is autosomal ___?

Answer 51

Autosomal dominant

Question 52

Prevalence of LDLR mutation causeing Familial hypercholesteroliemia?

Answer 52

= disorder with autosomal dominant inheritance > 1/500 (quite prevalent)

Question 53

What are some symptoms of familial hypercholesterolemia?

Answer 53

``` Heterozygous = Xanthelasma > progress to Xanthomas (demarcated yellowish deposit of cholesterol underneath the skin on or around the eyelids) Arcus Cornealis (single corneal circle of lipid deposits parallel to the limbus, ring of white on periphery of iris ``` Homozygous = early onset xanthomas, xanthomas at joints, hands, ankles