Clinical Significance Of Lipoproteins Flashcards
Framingham heart study
Monitors the development and progression of cardiovascular disease over three generations
- revealed major CVD risk factors to be the following
1) increased blood pressure
2) increased blood triglyceride levels
3) increased cholesterol leaves
4) decreased high density lipoproteins
5) increased low density lipoproteins - first study to demonstrate an inverse relationship between HDL concentrations and chances of having coronary heart disease (CHD)
- patients that have low LDL and low HDL have almost as high of a chance of getting CHD as patients with high LDL and low HDL*
Framingham heart study specific statistics
1) suggest that the prevalence of CHD increases by 25-30% every 10mg decrease in HDL
2) more than 50% chance of having CHD in patients with <45mg of HDL
3) patients who have low LDL levels (<100mg) still have an increased risk of CHD and atherosclerosis if HDL levels drop
How do cells respond to a drop in intracellular concentration of cholesterol?
1) making new cholesterol via de novo synthesis from acetyl-CoA
2) import cholesterol from LDL in the blood via endo cytosol using LDL receptors
What gene regulates LDL uptake?
Sterol regulatory element-1 gene (SRE-1)
- more active = increased LDL removed from blood and excreted via liver metabolism- reduces CHD risk
Cholesterol uptake vs synthesis
Cholesterol uptake is regulated via controlling the rate of SLE-1 gene action and the reduction of HMG-CoA reductase via allosteric inhibition
- inhibiting HMG-CoA is when intracellular cholesterol levels are high only
- increasing SLE-1 gene activity is when the intracellular cholesterol levels are low
Steps in receptor mediated endocytosis of LDL
1) LDL receptors found in clathrate-coated pits on cell surfaces bind to LDL molecules via apoprotein B-100 in th eLDL
2) once bound LDL-B-100 complex is endocytosed
3) forms vesicles called endoscope sin cells
4) pH of the endoscope falls which allows separation of LDL from the receptor, allowing the receptor to bind more LDL (whereas the previously bound LDL remains in the endoscope)
5) LDLs in endoscope are degraded via lysosomes, and receptors can be recycled if needed
Familial hypercholesterolemia
Genetic disorder characterized by a wide variety of mutation on the LDL receptor gene (primarily the PCSK9 mutation or app B-100 gene)
- all mutations present proper binding of LDL to the LDL receptor, allowing for a lot of excess LDL floating in the blood.
Heterozygous FH = 1:500
- treated via statins and PCSK9 inhibits, doesn’t usually kill
Homozygous FH = 1:1,000,000
- often kills and does not respond to drug therapy
- needs LDL apheresis and liver transplantation as modes of treatment
Drugs that increase HDL-cholesterol
PPAR-alpha activators (fish oils/ fibrates)
Niacin
CETP inhibitors
Drugs that lower LDL-cholesterol
STATINs
Cholesterol absorption inhibitors (ezetimibe)
Bile acid binding resins
(Colestipol, cholestyramine)
PCSK9 inhibitors
( Praluent and repatha)
STATINs MOA
Statins act as competitive inhibitors for HMG-CoA reductase enzyme, inhibiting it
- this prevents cholesterol synthesis in the liver.
- significant since most LDL circulating in the blood is synthesized rather than taken in by dietary means
Also work to increase activation of SRE-1 gene which increases LDL receptor production
HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis
Pleiotropic effects of statins
Pleiotropic = additional effects on other systems that may or may not be beneficial
- in this case all are good
Improve endothelial function
Enhance plaque stability (prevent thrombosis)
Decrease oxidative stress, inflammation, thrombogenic response
Beneficial effects on immune system, CNS, and bone
ADRs of statins
Muscle/joint pain ( most common side effect but only 10% occurrence)
Rhabdomyolysis (1:10,000)
Mind/memory issues (this is not 100% proven)
Increases blood sugars (bad for diabetics)
- Cana Leo slightly increase chances of type 2 diabetes
May or may not cause liver damage
What statins have the longes half life?
Rosuvastatin (Crestor)
- t1/2 = 19hrs
- most efficacious
atorvastatin (Lipitor)
- t1/2 = 14hrs
- 2nd most efficacious
- less ADRs than rosuvastatin
- most profitable drug in the history of pharm
- these dont have to be taken at night*
What statins have the shortest life?
Simvastatin
- t1/2 = 2hrs
Pravastatin
- t1/2 = 2hrs
Lovastatin
- t1/2 = 2hrs
Fluvastatin
- t1/2 = 1 hr
- all need to be taken at night only*
Affects of Ezetimibe
Blocks uptake of dietary cholesterol in the intestines via blocking the NPC1L-1 protein receptor
- causes this cholesterol to be excreted and forces the liver to absorb more cholesterol from the blood stream, hence lowering VDL in the blood stream
- MOST commonly 2nd added statin*
- only time monotherapy is recommended is patients who have primary hypercholesterolemia and cant tolerate statins
Fibrates MOA
Alter gene transcription for encoding protiens that increase HDL levels
- done by hyper activating the PPAR-a gene
2013 ACC/AHA cholesterol guidelines
1) always recommend heart healthy lifestyle changes
2) assess 10-year ASCVD risk every 4-6 yrs in patients older then 40
3) high-intensity stains are used with those with CVD and older than 75 yrs
4) high-intensity statins are also used in patients with LDL counts >190mg
5) moderate- intensity statins are used in patients 40-75 yrs old with a >7.5% 10 yr risk of ASCVD
- based on these guidelines, everyone over 60yrs old would be on a statin*
- overestimates the risk by 75-150%
Role of PCSK9 in regulating LDL
PCSK9 binds to LDL receptors and prevents receptor recycling from the endosome -> the cell surface
- causes the LDLR-LDL complex to not be removed and both are degraded in the lysosome
PCSK9 proteins are mainly expressed in the liver, intestine, kidney and CNS tissues
Role of PCSK9 inhibitors in lowering LDL
Are given subcutaneously IM once or twice a month
- often used w/ statins as combination therapy
Help boost the efficacy of statins as well as prevent LDLR degradation
Significance of lipoproteins
Most storage of energy is in lipids due to efficiency.
- have higher energy content and ATP yield per gram compared to carbs or proteins
- This is because lipids are much more reduced and have available bonds for energy (more carbons)
lipids are not very soluble in water and therefore cannot travel through the blood without binding.
Types of lipids in body
Fatty acids (5%) -transported through the blood via serum albumin
Cholesterol (50%)
TGs (20%)
Phospholipids (30%)
all lipids other than FAs are transported via lipoproteins
Anatomy of a lipoprotein
Inside consists of esterfied cholesterol and TAGs
Outside consists of phospholipids and free cholesterol (with OH groups facing the blood)
- also contain peripheral apoprotein on the outside and integral proteins on the inside
What does each type of lipoprotein carry primarily?
Chylomicrons and VLDLs = triacylglycerols (dietary and endogenous respectively)
-these are the 2 largest Lipoproteins
LDL and HDLs = cholesterol
- LDL delivers cholesterol to free tissues whereas HDLs remove excess cholesterol from tissues and bring it back to the liver
- these are the two smallest lipoproteins
note TGs cannot enter cells unless they are degraded extracellularly into FFAs and glycerol backbone
Types of lipoproteins and the specific apolipoproteins associated w/ them and the source of production in the body
Chylomicrons = intestines
- possess B-48 apolipoproteins
VLDL = liver/intestines
- possess B-100 and C2 apolipoproteins
LDL = comes from degraded VLDLs
- also possess B-100 but no C-2 apolipoproteins
HDL = liver/intestines and degraded chylomicrons
- possess A-1/ C-2/ E apolipoproteins
How are dietary fats transported through the body?
1) Intestinal mucosal cells secrete nascent rich chylomicrons which bind to TAGs from dietary fats
2) Apo C-2 and apo E proteins from HDL bind to chylomicrons and make it a functional chylomicron that can traverse the bloodstream.
3) TAG rich chylomicrons traverse the blood stream and drop off TAGs to cells that are presenting Lipoprotien Lipase (LPL) enzymes
- LPL enzymes hydrolyze TAGs from chylomicrons that possess Apo C-2 proteins and make them into both FFA components to be brought in intracellularly and glycerol to the liver to be digested
4) A chylomicron protein becomes a remnant once about 90% of the TAGs are hydorlyzed, they lose the Apo C-2 protien and are transported back to the liver and endocytosed
Why does cardiac muscle cells have the highest LPL enzyme levels?
Because the primary source of energy for cardiac cells are Fatty Acids (FAs)
- Also, insulin works by upregulating LPL levels on fat cells*
How are endogenous fats transported through the body?
1) liver secretes nascent rich VLDL particles that have high levels of endogenous TAGs
2) VLDLs pick up apo C-2 and apo E proteins from HDL to become functional VLDLs
3) functional VLDLs traverse the blood stream, binding to LPL presenting cells throughout the body
- LPL enzymes hydrolyze TAGs from chylomicrons that possess Apo C-2 proteins and make them into both FFA components to be brought in intracellularly and glycerol to the liver to be digested
4) once a VLDL has exhausted roughly 90% of the TAGs, the VLDL releases the Apo C2/E proteins and becomes LDL proteins that are then endocytosed in liver cells/tissues
Hepatic steatosis
Causes non-alcoholic fatty liver due to the liver producing too much TAGs and not enough VLDL
- the over production of TAGs causes the liver to endocytose intracellular TAGs in extrahepatic tissues
How is cholesterol synthesized in cells?
Via acetyl CoA substrate using HMG CoA reductase
- all cells that functionally need cholesterol can do this (provided acetyl CoA levels are high enough)
- this means that dietary cholesterol is not needed to survive
How are intracellular cholesterols stored?
Via Acyl CoA cholesterol acytransferase enzymes (ACAT)
Excess free cholesterol is esterfied via ACATs and stored in cellular endosomes
How does HDL take cholesterol from tissues and transport it to the liver?
1a) Use apo C-1/E proteins that are naturally on them to bind free cholesterol
- this cholesterol is immediately esterfied on HDLs via lecithin:cholesterol acyltransferase (LCAT) enzymes.
* these enzymes are produced in the liver and bind to HDL via the apo A-1 proteins*
1b) also can take cholesterol from peripheral tissues via ABCA1 (more common) or ABCG1 proteins
2) as HDL molecules gain more esterfied cholesterol they become HDL 2 -> HDL3 molecules
4) Cholesterol ester transfer protein (CETP) take cholesterol esters from HDL to VLDL in the liver, where the VLDL is endocytosed and the cholesterol esters are catabolizd
5) HDL keeps going freely in the bloodstream
Broad Concentrations of each lipoproteins
HDL:
- primarily proteins and cholesterol
- lowest TAG content
LDL:
- highest cholesterol content
- Low TAG content
VLDL:
- Low cholesterol content
- High TAG content
Chylomicrons :
- lowest cholesterol content
- Highest TAG concentration
