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

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Flashcards in L39 – Unveiling the myth: the science of cholesterol and lipids Deck (53):
1

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

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

2

Name some functional molecules formed from cholesterol ?

Bile salts
Steroid hormones
Vitamin D
plasma membrane

3

What is glycoholic acid and what is it made of?

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

Made of cholic acid (sterol) and glycine

4

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

Cholesterol esterase

Cholesterol ester + water > free cholesterol + fatty acids

5

Dietary cholesterol intake influence plasma LDL cholesterol?

Dietary cholesterol intake increase = little influence on plasma LDL cholesterol

6

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

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

7

products of pancreatic lipase catalysis of TAG?

TAG > 2-Monoacylglycerol + fatty acids

8

What are the primary products of small intestine digestion?

Free fatty acids
Cholesterol
2-monoacylglycerol

9

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

Immediately reesterify
primary products for
packaging into chylomicrons

Free cholesterol convert to Cholesterol ester by ACAT2 enzyme

10

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

Apo B-48
Phospholipids
TAG
Cholesterol ESTER
fat soluble vitamins

11

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

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

12

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

NPC1L1 receptor

enter through endocytosis

13

Where do chylomicrons carry CE to?

Lymphatic system> blood > hepatocytes

14

How can bile acid exit blood and be excreted?

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

15

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

Recycled back into blood when dietary intake of fat happens

16

Which form of cholesterol is majority in body?

85 - 90% Free cholesterol

10-15% CE

17

How does age relate to increase dietary cholesterol absorption?

Increase age = increase NPC1L1 expression = increase dietary cholesterol absorption

18

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

by taking drug: Ezitimibe

19

What microbe can modify bile acids in intestines?

Gut flora with Bile Acid Hydrolase

20

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

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

21

Consequence of overall reabsorption of bile acids to extrahepatic circulation ?

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

22

How does age affect plasma LDL levels via gut flora?

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

23

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

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

24

What lipoprotein carries cholesterol from peripheral tissue to liver?

HDL

25

What are the 2 sources of cholesterol inside hepatocyte?

From peripheral tissue delivered via HDL (or remodeled VLDL...)

Cholesterol synthesis inside hepatocyte

26

Which lipoprotein can linger in plasma?

LDL

27

What carries LDL into hepatocyte?

LDLR
(LDL receptor )

28

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

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

29

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

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

30

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

High

31

Number of stages in cholesterol synthesis inside hepatocyte?

4

32

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

Stage 1

33

What does stage 1 of cholesterol synthesis inside hepatocyte involve?

Conversion of 3 molecules of acetyl CoA to MEVALONIC ACID

34

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

HMG-CoA synthase + HMG-CoA reductase


HMG-CoA reductase

35

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

HMG-CoA reductase targeted to stop cholesterol synthesis at stage 1 (cannot produce mevalonic acid

Statin is a competitive inhibitor

36

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

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

Glucagon limit activity

37

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

Insulin stimulates phosphatase that dephosphorylate inactive reductase to active form

38

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

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

39

What happens in stage 2 of cholesterol synthesis in hepatocyte?

Formation of activated ISOPRENE UNITS from mevalonic acids

Requires lots of ATP and oxygen

40

What happens in stage 3 of cholesterol synthesis in hepatocyte?

form SQUALENE from 6 isoprene units

41

What happens in stage 4 of cholesterol synthesis in hepatocyte?

Cyclization reaction steps convert squalene to Cholesterol

42

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

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

43

3 ways cholesterol synthesis is regulated?

Sterol-dependent regulation of gene expression

Sterol- accelerated enzyme degradation

Sterol- independent phosphorylation/ dephosphorylation

44

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

Thyroxine

Insulin

45

How does Sterol -accelerated regulation of cholesterol synthesis work?

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

46

How does Sterol-dependent regulation of gene expression work?

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

47

What are the 2 mechanisms of cholesterol removal from liver?

1. Direct efflux through gallbladder to small intestine

2. Conversion to bile acids > efflux to gallbladder

48

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

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

49

What type in Frederickson classification is familial hypercholesterolemia?

IIa

50

Cause of Familial
hypercholesterolemia?

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

51

FH is autosomal ___?

Autosomal dominant

52

Prevalence of LDLR mutation causeing Familial hypercholesteroliemia?

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

53

What are some symptoms of familial hypercholesterolemia?

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

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