Flashcards in L39 – Unveiling the myth: the science of cholesterol and lipids Deck (53):
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
Name some functional molecules formed from cholesterol ?
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
Name of enzyme for converting cholesterol ester to free cholesterol for absorption?
Cholesterol ester + water > free cholesterol + fatty acids
Dietary cholesterol intake influence plasma LDL cholesterol?
Dietary cholesterol intake increase = little influence on plasma LDL cholesterol
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
products of pancreatic lipase catalysis of TAG?
TAG > 2-Monoacylglycerol + fatty acids
What are the primary products of small intestine digestion?
Free fatty acids
What happens to primary products in intestine? What happens to free cholesterol in enterocyte?
primary products for
packaging into chylomicrons
Free cholesterol convert to Cholesterol ester by ACAT2 enzyme
In the intestinal mucosal cell, what 5 things are incorporated into a chylomicron? (exogenous)
fat soluble vitamins
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
What is the channel for transporting free cholesterol into intestinal mucosal cells?
enter through endocytosis
Where do chylomicrons carry CE to?
Lymphatic system> blood > hepatocytes
How can bile acid exit blood and be excreted?
From hepatocyte > blood > enterocyte > NPC1L1 receptor > intestinal lumen > excreted
When is bile acid in the intestine lumen reabsorbed for use?
Recycled back into blood when dietary intake of fat happens
Which form of cholesterol is majority in body?
85 - 90% Free cholesterol
How does age relate to increase dietary cholesterol absorption?
Increase age = increase NPC1L1 expression = increase dietary cholesterol absorption
What can inhibit NPC1L1 to cause decrease in LDL-C in plasma?
by taking drug: Ezitimibe
What microbe can modify bile acids in intestines?
Gut flora with Bile Acid Hydrolase
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
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
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
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
What lipoprotein carries cholesterol from peripheral tissue to liver?
What are the 2 sources of cholesterol inside hepatocyte?
From peripheral tissue delivered via HDL (or remodeled VLDL...)
Cholesterol synthesis inside hepatocyte
Which lipoprotein can linger in plasma?
What carries LDL into hepatocyte?
(LDL receptor )
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
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
Increased LDL residence time and decreased LDL clearance lead to what level of LDL in plasma?
Number of stages in cholesterol synthesis inside hepatocyte?
Which of the stages of cholesterol synthesis inside hepatocyte is rate-limiting?
What does stage 1 of cholesterol synthesis inside hepatocyte involve?
Conversion of 3 molecules of acetyl CoA to MEVALONIC ACID
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
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
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
How does insulin promote HMG-CoA reductase acitivty in short-term cholesterol regulation?
Insulin stimulates phosphatase that dephosphorylate inactive reductase to active form
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
What happens in stage 2 of cholesterol synthesis in hepatocyte?
Formation of activated ISOPRENE UNITS from mevalonic acids
Requires lots of ATP and oxygen
What happens in stage 3 of cholesterol synthesis in hepatocyte?
form SQUALENE from 6 isoprene units
What happens in stage 4 of cholesterol synthesis in hepatocyte?
Cyclization reaction steps convert squalene to Cholesterol
Give the end-products of each stage of cholesterol synthesis in hepatocyte?
Acetyl CoA > Mevalonic acid > Isoprene units > Squalene > Cholesterol
3 ways cholesterol synthesis is regulated?
Sterol-dependent regulation of gene expression
Sterol- accelerated enzyme degradation
Sterol- independent phosphorylation/ dephosphorylation
What molecules upregulate expression of gene for HMG-CoA reductase?
How does Sterol -accelerated regulation of cholesterol synthesis work?
Increase in cholesterol conc. > acitvate degradation of HMG-CoA reductase at ER > less cholesterol synthesis
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
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
What chemical is used for gallbladder response to release hepatic cholesterol?
gallbladder responses to cholecystokinin (hormone) > releases hepatic
cholesterol into small intestine
What type in Frederickson classification is familial hypercholesterolemia?
Cause of Familial
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
FH is autosomal ___?
Prevalence of LDLR mutation causeing Familial hypercholesteroliemia?
= disorder with autosomal dominant inheritance > 1/500 (quite prevalent)