Cholesterol & Phospholipids Flashcards
Hypercholesterolemia
High LDL (“bad cholesterol”) raises Cardiovascular disease risk
Primary hypercholesterolemia - genetic defect and presents in infancy
Secondary hypercholesterolemia - presents in adulthood because of sedentary lifestyle, cholesterol rich diet, and smoking
How much cholesterol in the body is synthesized in the liver?
Half
What drugs can lower LDL cholesterol by inhibiting endogenous cholesterol synthesis. How?
Statins. They inhibit HMG-CoA reductase that produces cholesterol
What is good about cholesterol?
Modulates membrane fluidity and membrane protein activity
Substrate for steroid hormone synthesis in skin and endocrine tissues
Substrate for synthesis of emulsifier for dietary fat in the liver –> bile
Why is too much cholesterol bad?
Excess LDL is taken up by macrophages and seeds plaques in blood vessels which predisposes someone to cardiovascular disease
When and where is cholesterol made?
Made in liver during the fed state
What is cholesterol?
Isoprenoid - not a fatty acid or a carb
How is cholesterol synthesized?
Isoprenoid synthesis begins with acetyl-CoA
Begins with condensation reaction of 3 acetyl-CoA molecules to hydroxymethyglutaryl-CoA
HMG-CoA is then converted to mevalonic acid by HMG-CoA reductase
What is the committed step of cholesterol synthesis?
HMG-CoA reductase
What does HMG-CoA reductase yield?
Isoprenoids (cholesterol)
What does HMG-CoA lyase yield?
Ketone bodies
What regulates HMG-CoA reductase?
- Phosphorylation - AMPK activates in response to low energy
- Protein expression (insulin/glucagon) - insulin increases protein amounts and glucagon decreases
- Inhibited by statin drugs and cholesterol
Inactive in fasting or low energy state
What happens after HMG-CoA reductase produces mevalonic acid?
Mevalonic acid converted into dimethylallyl PP and isopentenyl PP (5 carbons each)
Two dimethyallyl PP and one isopentenyl PP make farnesyl pyrophosphate (15 carbons)
What is farnesyl PP an important precursor for?
Coenzyme Q for e- transport
Dolichol phosphate for protein glycosylation
Lipid anchor for peripheral membrane proteins
What occurs with insufficient cholesterol synthesis?
Affects electron transport and post-translational protein modification
How is farnesyl PP converted to cholesterol?
2 farnesyl PP are condensed to form squalene and then intramolecular rearrangements produce lanosterol (30 carbons)
Cholesterol (27 carbons) results from enzymatic modifications of lanosterol
Explain the process of storing cholesterol
Cells acquire cholesteryl esters (CE) from LDL by receptor mediated endocytosis
LDL digested in lysosome and cholesterol released into cytosol
LDL receptor recycled to the surface
Acyl-CoA cholesteryl acyltransferase produces cholesteryl ester for storage in droplets
Lipid droplets contain cholesteryl esterase for eventual cholesterol release
What does it mean for a cell if they have more LDL receptors?
Higher uptake of cholesterol esters from LDL
What do drugs for lower cholesterol also target in relation to LDL?
LDL receptor cycling so that more cholesterol is not stored
What types of cells have lots of acyl-CoA cholesteryl acyltransferase?
Steroid hormone producing cells
Explain the process of excreting cholesterol
Two step reaction - increases amphipathic properties
- Cholesterol converted to 7alpha-Hydroxycholesterol by 7alpha-hydroxylase
- Addition of taurine or glycine that forms primary bile acids in gall bladder
What are bile acids?
Bile acids are produced by the liver to emulsify dietary fat and they break up big drop to give access to lipases
After 7apha-hydroxycholesterol is converted to chenodeoxycholic acid or cholic acid. Taurine or glycine is added. What are the products when taurine or glycine is added? What happens to them?
Addition of taurine - Taurochenodeoxycholic acid or taurocholic acid
Addition of glycine - glycochenodeoxycholic acid or glycocholic acid
These are the primary bile acids in gallbladder and they are secreted in bile together with cholesterol, phospholipids, fatty acids, and salt
They are then modified and taken up to form the secondary bile acids in the gut, which re-enter through enterohepatic circulation
Secondary Bile Acids
Bile acids that are taken up through enterohepatic circulation and can act as steroid hormones
In the liver and intestinal cells, bile acids bind to farnesoid X receptor (FXR) and inhibit fatty acid synthesis via steroid response element binding protein (SREBP1)
What does FXR signaling inhibit?
Bile acid production
What does the microbiome have to do with bile acids?
Microbiome can produce secondary bile acids with different hormonal activities. Gut microbes affect host gene expression
What is going on with a patient who present with sharp pain in upper right quadrant and nausea? Pt also has jaundice elevated serum bilirubin, and elevated alkaline phosphatase.
Indicate cholestasis (gall stones) and bilirubin and alkaline phosphatase not secreted into gut
What causes gall stones?
Gall fluid contains cholesterol, bile acids, phospholipids, and bilirubin
Cholesterol in bile is close to precipitation point so small changes in bile secretion or bile metabolism can produce cholesterol stones in bile. Not as common is precipitation of bilirubin
Can be treated with ursodeoxycholic acid to dissolve stones
What do the bulk of biomembranes consist of?
Phospholipids - two fatty acids and a phosphate containing polar head on a glycerol backbone
What are the lipids common in different membranes?
Phospholipids - Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylinositol (PI), Phosphatidylserine (PS), and cardiolipin (CL)
Cholesterol - CHOL
Sphingolipids - SM
What is the lipid composition of the plasma membrane and mitochondrial membrane?
Plasma membrane is rich in sphingolipids, cholesterol and plasmologens. Has lipids with signaling function
Mitochondrial membranes are rich in cardiolipin
How are phospholipids synthesized?
Begin with phosphatidic acid
Activation of one of the components by binding to a CTP nucelotide
PI and Cardiolipin syntehsized from activated Diacyl Glycerol
PC, PE, and PS are synthesized from activated choline/ethanoalamine
What is the role of CTP in phospholipid synthesis?
PI and cardiolipin - CDP binding used to activate the lipid DAH
PC and PE - CDP binding used to activate the head group
Explain synthesis of cardiolipin and phosphatidylserine
Inner mitochondrial membrane is rich in cardiolipin - two phosphatidic acids connected with glycerol
PS made from PC or PE via head group exchange or carboxylation. PE +serine -> PS + ethanolamine. PC + serine -> PS + choline
