Lipids (Week 3 and 4--Edwards) Flashcards
Lipid disorders
Cardiovascular disease (hyperlipidemia, heart attack, stroke)
Obesity (linked to metabolic syndrome and diabetes)
Non alcoholic fatty liver disease (66% of diabetics have this)
Gall stones (can be fatal if block pancreatic duct and thus cause pancreatitis)
Minor diseases: Crohn’s disease, ileal resection, peroxisomal defects, respiratory distress syndrome, sphingolipidoses/defective degradation of substrates in lysosomes (Niemann-Pick C, Tay Sachs)
What exactly is a lipid?
There are hundreds/thousands of lipids and we don’t know the function of many of them
Includes: fatty acids, triglycerides, cholesterol, cholesterol esters, phospholipids, glycolipids, sphingolipids
Lipids are soluble in non-polar solvent but insoluble in water (except very short chain fatty acids)
What are lipids synthesized from?
Acetyl CoA
Acetyl CoA –> fatty acids –> triglycerides, phospholipids, sphingolipids, glycolipids, glycosphingolipids
Acetyl CoA –> cholesterol –> bile acids (in liver) or steroid hormones (in adrenals, testes, ovaries)
How do we absorb medium chain vs. long chain fatty acids?
Medium chain fatty acids/triglycerides: 6-12 carbons; do not require bile acids for hydrolysis in gut, so are absorbed directly into portal vein (ie milk)
Long chain fatty acids/triglycerides: 14-20 carbons; absorbed via chylomicrons
What are essential fatty acids?
FAs we don’t synthesize, so we need to eat them in our diet
Important for synthesizing arachidonic acid and other important fatty acids
What are saturated fatty acids?
Have no double bonds (saturated with as many hydrogens as they can)
Pack well
Found in meat
High dietary saturated fatty acids are risk factor for MI (whereas high dietary polyunsaturated FAs are protective)
Trans fatty acids
Produced by food industry (not natural) by partial hydrogenation to maintain better shelf life
Double bond is trans
Trans FAs increase risk of MI/heart attack
Triglyceride
Triglyceride (TG) AKA triacylglycerol (TAG)
3 fatty acids in ester linkage to 1 glycerol
Major dietary fat
Major storage fat
Phospholipids
Have glycerol, heterogeneous charged head group, 2 heterogeneous fatty acids
Lipases act on phospholipids to release fatty acids (could be arachidonic acid, which remember is precursor for thromboxanes, prostaglandins)
Cholesterol
Important for membrane fluidity
Precursor for bile acids/salt (thus important for lipid absorption), and for steroid hormones
Plasma lipoproteins
Have surface monolayer of specific proteins/apoproteins (may be structural, enzymes, enzyme activators, or recognition sites for cell surface receptors), phospholipids (polar, charged head group), cholesterol (which has hydroxyl group)
Core is tryglycerides and cholesterol esters (very hydrophobic)
Note: if cholesterol loses its hydroxyl group it will become a cholesterol ester and will go into core
What do plasma lipoproteins do?
Transport lipids through the blood
Lipids are transported within the plasma lipoproteins
Apoproteins on plasma lipoproteins (apoA-1, apoC-II, apoB) have specific functions involved in lipid metabolism, immunity, inflammation
What are the plasma lipoproteins we have?
HDL (good–correlates inversely with CHD)
VLDL (bad)
LDL (BAD–correlate with CHD)
Vary in size, density, composition, function
Are triglycerides correlated with heart disease?
Only very weakly
Digestion and absorption of lipid
1) Dietary lipids in intestinal lumen solubilized into micelles containing bile salts, then hydrolyzed to simpler lipids (FFA and monoglycerides)
2) Lipids enter enterocytes lining villi and complex lipids (triglycerides) re-synthesized and secreted into lymph as chylomicrons
3) Chylomicrons enter blood and deliver dietary lipid and fat soluble vitamins to other organs
Ezetimibe (aka Zetia)
Drug that inhibits cholesterol absorption (through NPC1L1)
Not used much any more because many risks, but is still on the market
How does pancreatic lipase work?
Pancreatic lipase cleaves 2 ester bonds to create 2 fatty acids and 1 monoacylglycerol
In the lumen of the intestine
How does cholesterol esterase work?
Cholesterol esterase cleaves an ester bond to release cholesterol and 1 fatty acid
In the lumen of the intestine
What does blood look like after a fatty meal?
Milky white-ish appearance because chylomicrons in there reflect light
TGA levels will be very high and provide no useful clinical information
How are chylomicrons removed from the blood?
1) Chylomicrons in bloodstream, and liproprotein lipase (in endothelial cells that line blood vessels of muscle and adipose tissue) with ApoCII cofactor (on surface of chylomicron) hydrolyzes triglycerides in core of chylomicron
2) FFAs enter muscle (for beta oxidation for energy) or adipose tissue for storage (after re-synthesis of TGs)
3) Chylomicron remnant is smaller and has less TGs, and is taken up by the liver by receptor-mediated endocytosis
What would happen if patient had inactive/mutant LPL (or mutation in ApoCII)?
Hyperchylomicronemia: too many chylomicrons in the blood (blood white because of chylomicrons even after 12 hour fast)
Can lead to pancreatitis (huge lipoprotein particles stuck in vessels of pancreas); can lead to Xanthomata (bumps on skin that are TG deposits)
Treatment: low fat diet (still need some fat for essential fatty acids)
Obvi would have high TG in blood
What happens to a diabetic with low insulin (Type 1 Diabetes) in terms of LPL activity?
LPL requires insulin, so LPL activity decreases if no insulin (essentially like having inactive/mutant LPL)
If uncontrolled Type 1 Diabetes, can get hypertriglyceridemia and hyperchylomicronemia –> pancreatitis, xanthomata
A-beta-lipoproteinemia
Defect in gene (MTP: microsomal triglyceride transfer protein; causes decreased ApoB-100 and apoB-48) so cannot package TGs into chylomicrons to secrete chylomicrons from enterocytes into liver
No VLDL in plasma, and enterocytes loaded with lipid because can take up lipid but can’t get rid of it
Leads to steatorrhea
What does the liver do regarding VLDL, LDL, HDL?
Liver secretes VLDL –> LPL can act on VLDL to make TGs to give to cells (well, must break down into FFAs first) –> then VLDL turns into LDL and LDL can go to cells to contribute its cholesterol or can go back into liver
Liver also creates HDL, which can go to cells and be anti-inflammatory and take cholesterol from peripheral tissue back to liver to be secreted in bile
Where are LDL receptors located?
1) On peripheral tissues so LDL can go into tissue to give cells cholesterol for cell division
2) On liver (lots) so liver can take up LDL and get rid of the cholesterol in it by secreting it as bile or bile acids
What are similarities and differences between chylomicrons and VLDL?
Chylomicrons secreted by enterocytes, and release FFAs to go into adipose tissue/muscle while leaving behind a chylomicron remnant
VLDL is secreted by the liver and also releases FFAs to go into adipose tissue/muscle but leave behind an LDL (which goes to liver or peripheral tissue)
Both are acted upon by LPL and ApoCII
What do LDL and VLDL have in them?
LDL has cholesterol ester (because gives bad cholesterol to cells!)
VLDL has TGs (because just giving TGs/FFAs to cells)
What controls LDL levels in the plasma?
Partially by synthesis of VLDL (and thus LDL) and partially by hepatic expression levels of LDL receptor (LDLR) that clears LDL from blood
How do cells get their cholesterol?
1) LDL receptor on cell surface endocytoses LDL, turns into lysosome that secretes cholesterol into cytoplasm
2) Cell can synthesize cholesterol from acetate, and enzyme to regulate this is HMG-CoA reductase
Note: these two things go up and down together–if the cell needs more cholesterol, it uses both these pathways to get it
What happens to cholesterol once it’s in the cell?
Depends on what cell it’s in!
Liver can turn cholesterol to bile acids to secrete it
Adrenal cells can turn cholesterol to steroid hormones
etc etc
How important is the LDL receptor in controlling plasma LDL levels?
Very important!
Mutation in LDL receptor gene (Familial Hypercholesterolemia) thus less LDL receptor on liver, means increased plasma LDL (and higher risk for heart attack)
More LDL receptor on liver means decreased plasma LDL (and lower risk for heart attack)
What do statins do?
Statins add LDL receptors to the liver to remove more LDL from blood
Reduce plasma LDL 20-50%, and thus reduce risk of heart attack
Can you be homozygous for a mutation in the LDL receptor (Familial Hypercholesterolemia)?
Yes, but you have REALLY high LDL and total cholesterol, and can get heart attack REALLY young (younger than 13)