Cholesterol Flashcards
Which 3 sources are fats derived from
Diet
De novo biosynthesis
Adipose tissue
Which group of enzymes break down dietary fats?
Lipases
What is the role of bile salts?
To emulsify fats aiding digestion and absorption (also of fat-soluble vitamins)
Which vitamins are fat soluble?
A, D, E and K
What is the result of lack of bile salts?
Majority of fat passing the gut undigested resulting in steatorrhea (fatty stool)
What is steatorrhea?
Excretion of fatty stool due to incomplete digestion of fats
Where is bile salt produced and stored?
Produced in liver, stored in gallbladder
What is the oral medication that is effective in treating obesity by inhibiting gastric and pancreatic lipases called?
Orlistat aka tetrahydrolipstatin
How does orlistat help with weight loss?
Reduces fat absorption by 30% as it is a potent inhibitor of gastric and pancreatic lipase
What are the side effects of orlistat?
Main side effects include abdominal pain, urgency to defecate, increased flatus and steatorrhea
What is synthesised as a transport molecule for dietary fats?
Chylomicron (CM)
What is a CM composed of?
Triglycerides, apoproteins (from HDL) and phospholipids (enclosing the triglycerides)
What is the route CM follow?
travel from the lacteals of the intestine to the thoracic duct and to the left subclavian vein where they enter the bloodstream
Which enzyme hydrolyses CM?
Lipoprotein lipase through recognition of apoproteins
Where is lipoprotein lipase found?
Located on the capillary endothelial cells lining a variety of tissues including adipose, heart and skeletal muscle
What happens to the contents of CM after hydrolysis?
Triglycerides → FA and Glycerol
FA undergo β-oxidation
Glycerol returned to liver for gluconeogenesis
What type of lipids is cholesterol?
Steroid
Where is majority of cholesterol located in?
More than 90% of cholesterol in the body is found in cell membranes regulating membrane stiffness bidirectionally
What is the dietary cholesterol uptake limit in humans approximately?
0.5 g/day
How are the physiological requirements for cholesterol supplied?
De novo synthesis of cholesterol from Acetyl CoA in the liver
What is the first of 3 main parts of cholesterol biosynthesis?
Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm)
What is the second of 3 main parts of cholesterol biosynthesis?
Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasm)
What is the third of 3 main parts of cholesterol biosynthesis?
Cyclisation and demethylation of squalene by monooxygenases to give cholsterol (ER)
Cholesterol Biosynthesis
Identify the step, enzyme and product
Step 1
Cholesterol Biosynthesis
Identify the step, enzyme and product
Step 2
Cholesterol Biosynthesis
Identify the step, enzyme and product
Cholesterol Biosynthesis
Identify the species providing negative feedback for this step
Cholesterol Biosynthesis
Which step is rate limiting in cholesterol biosynthesis?
Step 3 - Production of Mevalonate from HMG-CoA
Cholesterol Biosynthesis
What reactions does Mevalonate (6C) go through to produce isopentyl pyrophosphate (5C)?
Mevalonate undergoes sequential phosphorylation at hydroxyl groups at positions 3 and 5 followed by decarboxylation
Cholesterol Biosynthesis
Identify the groups of enzymes used in each step according to the reactants
3 Kinases and 1 Decarboxylase
Cholesterol Biosynthesis
What is the product of two consecutive condensation reactions of isopentenyl pyrophosphate (IPP)?
Farnesyl pyrophosphate (FPP) - 15C
Cholesterol Biosynthesis
Identify the enzyme and product
Cholesterol Biosynthesis
Identify the enzyme and product
Cholesterol Biosynthesis
Identify all the intermediate products
Which classes of steroid hormones arise from cholesterol?
What is the name of precursor of steroid hormones that is derived from cholesterol and which enzyme catalyzes this reaction?
Identify the condition needed to produce Vitamin D3 and the final product made from Vitamin D3?
What is the result of Vitamin D3 deficiency in childhood?
Rickets - softening and weakening of bones
What metabolism does calcitriol play a role in?
Calcium metabolism
What are the major breakdown products of cholesterol?
Bile salts
What are the source and role of VLDL?
Source - Liver
Role - Endogenous fat transport
What are the source and role of IDL?
Source - VLDL
Role - LDL precursor
What are the source and role of LDL?
Source - IDL
Role - Cholesterol transport
What are the source and role of HDL?
Source - Liver
Role - Reverse cholesterol transport
What are lipoproteins composed of?
Phospholipid monolayer containing cholesterol and apoproteins + a core of triacyl glycerols and cholesterol esters
What are the reactants and ezyme needed to produce cholesterol ester?
phosphatidylcholine (lecithin)
LCAT (lecithin cholesterol acyltransferase)
How is VLDL converted into LDL?
triacyl glycerols removed from VLDL → IDL → cholesterol esters added from HDL → LDL
What is meant by reverse cholesterol transport?
Function of HDL - collecting cholesterol from tissues. back to the liver
Why is LDL called bad cholesterol?
More than 40% of its weight is made up of cholesterol esters - elevated LDL levels lead to atherosclerosis
Which 2 lipoproteins provide FFA for the adipose tissue?
CM and VLDL
Which 3 lipoproteins provide FFA or cholesterol for the peripheral tissue?
CM, VLDL and LDL
Where are the CM remnants collected?
Liver
What happens to LDL remnants that are not cleared by the liver?
Cleared by macrophages
What is the inheritance pattern of familial hypercholesterolaemia (FH)?
Autosomal dominant
What is observed in patients with one or two copies of FH gene compared to non-carriers?
One mutant gene - serum cholesterol 2-3 times higher
Two mutant genes - serum cholesterol 5 times higher
Increased incidence of Atherosclerosis and coronary infarcts
What are the physiological symptoms of FH?
Xanthomas - deposition of extra cholesterol into macrophages of skin
Coronary Plaques - shown in picture B
Which molecule is affected in FH?
LDL receptor (LDLR)
How is LDL transported inside the cell?
Receptor mediated endocytosis
Identify the locations/types of mutations that result in FH
Identify appropriate outcomes of given mutations for FH
What medication could control hypercholesterolaemia by limiting cholesterol biosynthesis?
Statins - Lipitor (Pfizer) or Crester (AZ)
They behave in a similar way to Mevalonate to inhibit HMG-CoA Reductase in the rate-limiting step
What medication could control hypercholesterolaemia by limiting cholesterol reabsorption?
Resins/sequestrants - Cholestyramine (Questran, Prevalite)
They bind to bile acid-cholesterol complexes to prevent reabsorption by intestines
Lowers LDL by 15-30%
Raises HDL by 3-5%
