CV I - Hyperlipidemia Flashcards
What percent of deaths in a year are due to CV disease?
40%
What is the magnitude of increased risk for increases in serum cholesterol?
4-fold, upper vs. lower 10%
What are the four classes of circulating lipoproteins?
- Chylomicrons (Largest, triglyceride rich)
- VLDL
- LDL
- HDL (smallest, triglyceride poor)
Which apoproteins do chylomicrons and VLDL have?
- apo B-48
- apo B-100
- apo C
- apo E
What apoproteins do LDL have?
- Apo B-100
Which apoproteins do HDL have?
- Apo A-I
- apo A-II
- Apo C
- apo E
What does HDL do?
Takes excess cholesterol from the peripheral and brings it to the liver for metabolism and elimination (reverse cholesterol transport).
It acts with scavenger receptor-BI on the liver
Where is cholesterol generated?
Liver
Where are chylomicrons generated? What happens to them?
Generated in the GI tract from digesting fat.
They interact with lipoprotien lipase to liberate free fatty acids into peripheral tissue. Apolipoprotein C-LL (apo C-II) present on the chylomicron surface for this purpose.
Chylomicron remnant is taken up by the liver by receptor mediated endocytosis.
Where do VLDLs come from and where are they going?
Come from liver, go to peripheral tissue where they deposit fatty acids before becoming ‘VLDL remnants (IDL)’ in the blood and getting converted to LDL in the blood via removal of some apolipoproteins and lipolysis of remaining triglyceride.
What is cholesterol synthesized from? What is it metabolized to?
Liver synthesizes cholesterol from acetyl CoA.
Liver metabolizes cholesterol to form bile acids, which are sent to the duodenum and reabsorbed back to the liver for reutilization.
Give the synthetic pathway for hepatic cholesterol, including the rate limiting step.
- Acetyl CoA
- HMG-CoA
- HMG-CoA reductase converts HMG-CoA to cholesterol (RLS)
True or false? In addition to being metabolized to bile salts. Cholesterol can be deposited straight into the bile?
True
What do VLDLs do?
They transport lipids from the liver to other tissues. The majority of serum triglycerides are found in VLDL.
Where is the majority of circulating cholesterol found in humans?
In LDL
LDL are the primary means of delivery of cholesterol to peripheral tissues
Cholesterol uptake is achieved via LDL receptor-mediated endocytosis (50% by liver; remainder by other tissues)
How do HDL particles mature?
- Acquiring lipids (primarily cholesterol) from VLDL and chlyomicrons during lipolysis
- Acquiring cholesterol from peripheral tissues
What is type IIa hyperlipoproteinemia?
High levels of cholesterol (LDL) with no change to triglyceride level.
Also known as familial hypercholesterolemia if there is a LDL receptor mutation. But it is multifactorial (genetic or other)
It has a high incidence
What is type IIb hyperlipoprotienemia?
High LDL and VLDL elevates cholesterol AND triglyceride levels.
AKA familial combined hyperlipoproteinemia.
Characterized by incresed VLDL secretion.
It has a high occurrence of cardiovascular disease risk.
Which two hyperlipoproteinemias are the most commonly targeted by therapeutics?
Type IIa and IIb
What is an atherosclerosis?
- Reduction in blood flow leading to increased risk for CV disease (heart attack, stroke, kidney failure etc.)
- Consequence of aging, as well as certain factors (genetic and other)
List the risks for getting atherosclerosis
- Hypertension
- Hyperlipidemia
- Smoking
- Hyperglycemia
- Obesity
- Infection
- Inflammation
Give the steps for athersclerosis formation
- Injury to endothelium allows LDL to get into intima. It is oxidized (oxLDL) which causes immune response
- Foam cell formation (macrophage cells migrate from blood through tear in endothelium and uptake oxLDL, which is scavenger receptor mediated).
- Cholesterol stored as cholesterol esters (which can be removed by efflux to HDL, which is ABCA1 transporter mediated)
- Lysing of foam cells releases cholesterol esters back and further propagates the inflammatory response)
- Formation of necrotic core, fibrosis and advancement of lesion formation
What lipoprotein concentrations are positively correlated with risk for atherosclerosis?
- Serum total cholesterol
- Serum LDL
- Serum LDL:HDL
Give six categories for the treatment of hyperlipidemia
- Therapeutic lifestyle changes (TLC)
- Statins
- Niacins
- Bile acid binding resins
- Cholesterol absorption inhibitors
- Fibrates
What are statins?
Competitive inhibitors of HMG CoA reductase (RLS of cholesterol synthesis in the liver).
Primary therapeutic action is to increase hepatocyte LDL receptor levels to increase uptake of LDL into the liver and indirectly deplete cholesterol.
It is also anti-inflammatory and anti-coagulant
First choice for patients with elevated LDL
Why do statins show reduced benefits for patients that are homozygous for type IIa familial hypercholesterolemia?
They lack full LDL function, and statins have a high dependence on increased expression of LDL receptors.
What are three possible adverse effects of statins?
- Reversible liver toxicity
- Cardiomyopathy
- Drug interactions
However these are rare and statins are usually very well tolerated. They are the most effective drug for reduction of risk of death from CV disease.
What are niacins?
Water soluble vitamin (nicotinic acid)
These inhibit lipolysis (conversion of TG to free FAs). They can reduce LDL through a cascade of effects that eventually decrease hepatic VLDL and LDL synthesis.
What five things do niacins do at high concentrations?
Inhibit lipolysis in adipose tissue:
- Reduces circulating fatty acids
- Reduced hepatic TG biosynthesis
- Reduced hepatic VLDL synthesis and secretion
- Reduces serum LDL
- Increases serum HDL (don’t know how)
Niacin causes reduction of total plasma cholesterol and LDL. Why is its clinical use limited?
It is required in high doses.
can cause:
- Flushing
- Hot flashes
- GIT irritation
- Hepatotoxicity
What are bile acid binding resins and how do they work?
These are anion exchange resins that binds negatively charged bile acids in the small intestine, The resin/bile complex is excreted in feces, which prevents bile return to liver.
- This prevents feedback repression from bile acids, causing more bile acid synthesis, consequently reducing intracellular bile acid levels, intracellular cholesterol stores and increasing expression of LDL receptors.
Like in statins, increasing LDL receptors results in sequestering of LDL from the blood.
What are the names of the three most common bile acid binding resins?
- Cholestyramine
- Colestipol
- Colesevelam
What can affect compliance of bile acid binding resin takers?
- Palatability (taste bad)
- Bowel side effects (eg. diarrhea/constipation)
How can the efficacy of bile acid binding resins become limited?
There can be a compensatory increase in cholesterol biosynthesis.
What are cholesterol absorption inhibitors?
New (ezetimibe/Zetia). These are most effective when given with statins or niacins.
They inhibit cholesterol absorption from the small intestine from exogenous (dietary) and endogenous (bile) sources.
This depletes hepatic cholesterol, which results in increased LDL receptor expression and reduced serum total cholesterol and LDL. There is a minor beneficial effect on HDL and triglycerides.
What are fibrates?
These are orientated for patients for elevated triglyceride levels/reduced HDL, rather than elevated cholesterol.
Peroxisome proliferator-acivated receptor alpha agonists (nuclear receptor)
PPARalpha activation leads to increased expression of genes involved in lipid metabolism:
- endothelial lipoprotein lipase
- Hepatic fatty acid oxidation enzymes (reduces TG and VLDL synthesis)
- Hepatic apo A-I and A-II proteins
Which drug is best for anti-atherosclerosis effects?
Fibrates
- Increase chylomicron and VLDL clearance
- Reduce hepatic VLDL synthesis and secretion
- Promotes reverse cholesterol transport (HDL)
- Anti inflammatory
- Minimal effects on LDL because they increase metabolism of VLDL, which leaves intermediate density lipoproteins (IDL)
What are side effects of fibrates?
- GIT irritation
- Liver toxicity
- Rash
- Cardiomyopathy (rare) through toxicity to cells in the heart
True or false the combination of two or more drugs is often needed to treat hyperlipidemias
True
Type IIa: statins, resins, ezetimide, niacin
Type IIb: statins, resins, ezetimide, niacin, FIBRATES
How is familial hypercholesterolemia (type IIa) treated with reduced LDL receptor function and or expression
- Can cause childhood athersclerosis due to elevated total cholesterol and LDL
- Cholesterol lowering drugs are used in patients heterozygous (as they retain some response to statins or bile acid binding resins)
TLC plus niacin most effective (but limited)
In large part, atherosclerosis is a disease of the ____ (organ)
liver
