Flipped Classroom: Lipoproteins III Flashcards
The second receptor-mediated fate for circulating LDL is via the
Scavenger receptor
Has a lower affinity but broader specificity than the LDL receptor
Scavenger receptor
The scavenger receptor can recognize both
Normal and damaged LDL
Macrophages and some endothelial cell types possess the
Macrophage scavenger receptor (SR-A)
Significant percentages of LDL uptake in organs such as the intestine and spleen are accounted for by the
Scavenger receptor
SR-A has a higher affinity for
Oxidized (damaged) LDL
Leads to foam cell formation
SR-A
Even after mRNA has been fully processed, it may undergo additional posttranscriptional modification in which a base in the mRNA is altered. This is known as
RNA editing
The apoB mRNA is made in the
Liver and small intestine
However, in the small intestine only, the C residure in the codon CAA for glutamine is deaminated to U, changing this to a
Stop codon
This results in translation of the shorter protein known as
ApoB-48
What makes
- ) ApoB-100
- ) ApoB-48
- ) Liver (incorporated into VLDL)
2. ) Intestines (Chylomicron)
A circulating, abnormal varient of LDL
Lipoprotein(a) aka Lp(a)
Forms when ApoA forms a disulfide bonded complex with the ApoB-100 component of LDL
Lp(a)
A modest independent risk factor for atherosclerotic cardiovascular disease events, especially an MI
Lp(a)
Certain SNPs of the LPA gene maybe be associated with higher population risks for
CVD
VLDLs travel in the circulatory system until they associate with LPL. This association is mediated via
ApoC-II
Serves to remove excess cholesterol from the peripheral tissues and return it to the liver
Reverse cholesterol pathway
This movement is accomplished by
HDL
Transport of cholesterol from the liver to peripheral tissues is called
Cholesterol transport
While the transport of cholesterol from the peripheral tissues to the liver and steroid producing tissues is called
Reverse cholesterol transport
Formed in the blood by the addition of ipid to ApoA-I
HDL
Accounts for about 70% of the apoproteins in HDL
ApoA-I
Serves as a circulating reservoir of ApoC-II and ApoE
HDL
The apolipoprotein that is transferred to VLDL and chylomicrons and is an activator of LPL
ApoC-II
The apolipoprotein required for the receptor-mediated endocytosis of IDLs and chylomicron remnants
ApoE
Nascent HDL particles are derived from both the
Liver and intestine
Unlike the chylomicron and VLDL, the nascent HDL is not spherical but rather
Disc-shaped
Are also derived from surface components of both chylomicrons and VLDLs
HDL particles
ApoA-I activates
LCAT
ApoA-II activates
HL
Protein that is secreted by the liver and circulates in plasma, bound mainly to HDL
Cholesterol Ester Transfer Protein (CETP)
Promotes the redistribution of cholesterol esters, triglycerides, and, to a lesser extent, phospholipids netween plasma lipoproteins
CETP
The overall net effect of CETP is a net mass transfer of cholesterol esters from HDL to triglyceride-rich lipoproteins and
LDL
Also has the net effect of moving triglycerides from triglyceride-rich lipoproteins to LDL and HDL
CETP
Subsequently, the TAGs are removed from HDL by
HL
One consequence of these CETP-mediated transfers of cholesterol esters from HDL is a reduction in the cholesterol content and size of
HDL
The overall effect of CETP is a net mass transfer of cholesterol esters from HDL to
VLDL
The overall effect of CETP is also a net mass transfer of triglycerides from VLDL to
HDL
Nascent HDL form chiefly in the liver and intestine by loading phosphatidylcholine, cholesterol, and cholesterol esters onto
ApoA-I
Used by the liver to enrich discoidal HDL w/ phosphatidylcholine and cholesterol
ABCA1 transporter
When colesterol is taken up by HDL, it is immediately esterified by the plasma enzyme
LCAT
LCAT is synthesized and secreted by the
Liver
LCAT binds to nascent HDL and is activated by
ApoA-I
Transfers the fatty acid from carbon 2 of phosphatidylcholine to cholesterol, producing a hydrophobic cholesterol ester
LCAT
Whic HDL is more cholesterol ester rich, HDL3 or HDL2?
HDL2
CETP moves some of the cholesterol esters from HDL to VLDL in exchange for TAG, relieving product inhibition of
LCAT
Because VLDLs are catabolized to LDL, the cholesterol esters transferred by CETP are ultimately taken up by the
Liver
The uptake of cholesterol esters by thge liver is mediated by a cell-surface receptor
-Binds HDL
SR-B1
The HDL particle itself is not taken up. Rather, there is selective uptake of the cholesterol ester from the
HDL particle
With it’s ability to degrade both TAG and phospholipids, participates in the conversion of HDL2 to HDL3
HL
Elevation of plasma cholesterol, triglycerides (TGs), or both, or a low HDL level that contributes to atherosclerosis
Dyslipidemia
Can result from a single inherited gene defect, or more commonly, are caused by a combination of genetic and environmental factors
Primary hyperlipidemias
The result of a metabolic disorder such as DM, obesity, hypothyroidism, or primary biliary cirrhosis
Secondary hyperlipidemias
How do we calculate LDL cholesterol?
-the Friedewald equation (mg/dL)
LDL cholesterol = Total cholesterol - HDL - VLDL
The Friedewald equation is inaccurate when the concentration of triglycerides is high (greater than 400) or when there is an appreciable number of
Chylomicrons
How do we calculate VLDL cholesterol?
Total triglycerides/5
Patients who have hypertriglyceridemia mayhave normal or elevated
LDL cholesterol
Hypertriglyceridemia is defined as total plasma triglycerides in the fasting state in excess of
150 mg/dL
The hyertriglyceridemia is due to an abnormally high quantity of
Chylomicrons, VLDL, or both
The major risk of very severe hypertriglyceridemia is
Pancreatitis
Patients who hace very severe hypertriglyceridemia may also have
Eruptive and tuberous xanthomas
Characterized by the pathologic presence of chylomicrons after a 12-14 hour period of fasting
Familial chylomicronemia
In familial chylomicronemia, samples of lipemic plasma that are refridgerated overnight develop a
Creamy supernatant
When the plasma is tested, fasting triglyceride measurements are typically above
1000 mg/dL
Lowering of plasma triglycerides to below 500 mg/dL virtually eliminates a person’s risk of a repeat episode of hypertriglyceridemia-induced
Pancreatitis
Due to deficiency of LPL and ApoC-II activity
Familial chylomicronemia
Has secondary factors and a greater elevation of total cholesterol relative to that in familial chylomicronemia
Primary mixed hyperlipidemia
Characterized by the accumulation of remnants of chylomicrons and of VLDLs
Dysbetalipoproteinaemia
This is because Dysbetalipoproteinaemia develops due to a deficiency of
ApoE
Has a population prevalence of 1-2 in 20,000
Familial dysbetalipoproteinaemia
Plasma levels of LDL levels are decreased and plasma levels of IDL are increased because of interrupted processing of VLDL in
Dysbetalipoproteinaemia
An increased VLDL:triglyceride ratio and an ApoE homozygosity are therefore diagnostic for
Familial Dysbetalipoproteinaemia
The onset of Familial Dysbetalipoproteinaemia occurs after
Childhood
In women, onset of Familial Dysbetalipoproteinaemia is typically delayed until
Menopause
Clinical manifestations may very from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridemia is present
Familial Dysbetalipoproteinaemia
The cornerstone of treatment for hypertriglyceridemia
Lifestyle modification
Reduces VLDL production in a high dose
Statin
Increases LPL activity
Sipplement of fish oil rich in omega-3 FA
Activate PPARa transcription factors that lead to both increased lipoprotein lipase activity and an increased rate of fatty acid B-oxidation
Fibrate drugs
Works in part by activating niacin receptor 1 that inhibits lipolysis
Nicotinic acid (Vitamin B3)
People with hypercholesterolemia have a high risk of developing
Coronary artery disease
People that have two alleles for a defective LDL receptor have
Homozygous familial hypercholesterolemia
Have an LDL concentration that is 10x the normal concentration
Patients with Homozygous familial hypercholesterolemia
In less frequent circumstances, a patient can have Homozygous familial hypercholesterolemia due to two loss-of-function mutations in
ApoB-100
About 5% of heterozygous familial hypercholesterolemia pateints have a mutant
ApoB-100
About 2% of heterozygous familial hypercholesterolemia pateints have overactive
PCSK9 enzyme
Most patients who have heterozygous familial hypercholesterolemia have a mutant allele for the
LDL receptor
Patients with heterozygous familial hypercholesterolemia typically have how much more LDL than usual?
2x
Patients with heterozygous familial hypercholesterolemia that is untreated typically have heart attacks before their
Late 50’s
Patients with Homozygous familial hypercholesterolemia typically have heart attacks in their
Teens and twenties
The most common lipoprotein abnormality among pateints with CAD
Low HDL (less than 40 mg/dL)
Low HDL is also a component trait of the
Metabolic syndrome
The most common genetic disorder of HDL is
Familial hypoalphalipoproteinemia (FHA)
Common finding in patients with premature CAD
FHA
Results in a profound decrease in HDL (less than 5 mg/dL)
Complete loss of ApoA-1
ApoA-1 deficient patients can be distinguished from other causes of HDL deficiency by the complete absence of
ApoA-1
Patients with ApoA-1 deficiency also have normal levels of
LDL and TAGs
Patients with HDL deficiency due to ApoA-1 deficiency may also exhibit mild to moderate
Corneal opacification or corneal clouding
Another cause of low HDL is
LCAT deficiency
