Module 1: Deck 2/Cards 8-15 Flashcards
Which hyperlipoproteinemia = Patients often have and frequently similar levels of plasma TG and cholesterol, generally over 300mg/dL. Most have apo E2 polymorphisms and a second lipoprotein abnormality.
Dysbetalipoproteinemia (type III hyperlipoproteinemia)
What is dysbetalipoproteinemia characterized by?
it is a polygenic disorder characterized by abnormalities of binding of VLDL remnants and chylomicrons remnants to the hepatic remnant receptor, LDL related protein.
Dysbetalipoproteinemia (type 3)
Describe the findings on a basic lipid panel that would be consistent with this disorder.
Patients often have high and often equal elevation in plasma cholesterol and triglycerides, consistent with the equal concentration of cholesterol and TG in the lipoprotein remnant particles that characterize this disorder.
Dysbetalipoproteinemia: when would you want to draw an ApoE in these patients?
when they have palmar xanthomas.
Dysbetalipoproteinemia: what would you draw when a patient has palmar xanthomas.
ApoE
Where is ApoE primarily synthesized?
in the liver and small intestines
What is ApoE a component of ? (5)
- chylomicrons
- chylomicron remnants
- VLDL
- IDL
- a subgroup of HDL
What are the three common genetic variants of ApoE?
- ApoE-II least common
- ApoE-III most common
- ApoE- IV
ApoE-II differs from the most common isoform, ApoE-III by a single amino acid substitution where?
Where cysteine substitutes for arginine at residue 158.
ApoE-IV differs from ApoE-III where?
at residue 112, where arginine substitutes for cysteine
(1) and (2) are ligands for the LDL receptor while (3) is poorly recognized by the LDL receptor.
- Apo E-III
- Apo E-IV
- Apo E-II
What is Apo E-IV associated with? 2
Alzheimer’s and atherosclerosis
What isoform/isotype do Dysbetalipoproteinemia often have?
homozygous apolipoprotein E isotype E-II-E-II (others have been reported)
What co-factors may cause palmar or tuberoeruptive xanthomas and premature CAD in Dysbetalipoproteinemia pts? 6
- hypothyroidism
- DM 2
- obesity
- renal impairment
- drug effects
- concomitant familial combined hyperlipidemia
Dysbetalipoproteinemia: In the absence of concomitant additional abnormalities in lipoprotein metabolism, normal or even lower than normal LDL-C levels may be seen. Why
possibly related to an up-regulation of hepatic LDL receptors.
Which hyperlipoproteinemia = usually presents during infancy or early childhood with acute abdominal pain, eruptive xanthomas and with a 10-1 ratio of TG to cholesterol?
Type 1 hyperlipoproteinemia AKA familial hyperchylomicronemia
Type I hyperlipoproteinemia is a rare ______ disorder? 3
monogenic, autosomal recessive
Type I hyperlipoproteinemia or familial hyperchylomicronemia is often diagnosed at what age?
infants or very young children.
Type I hyperlipoproteinemia or familial hyperchylomicronemia is characterized by what?
Excessive quantities of circulating chylomicrons, particles that contain triglycerides and cholesterol in a ratio of 8 or 10 to 1, accounting for similar ratio and the circulating concentrations of these 2 lipids
Type I hyperlipoproteinemia or familial hyperchylomicronemia: Patients with this disorder may have what signs and symptoms? 3
- recurrent abdominal pain with pancreatitis,
- eruptive xanthomas, and
- lipemia retinalis.
Type I hyperlipoproteinemia or familial hyperchylomicronemia: what is this caused by? 2
- A complete absence of lipoprotein lipase activity
2. or less frequently by genes coding for other proteins needed for LPL function
Type I hyperlipoproteinemia or familial hyperchylomicronemia: how do you treat this? 2
- A strict low-fat diet is required to aid in symptomatic relief.
- Gene therapy implying an LPL gene variant has been approved to treat this disorder in Europe but there are no approved medical treatments in the US.
apoC-III antisense antibody therapy
- Which hyperlipoproteinemia = Usually characterized by elevated triglycerides but normal ApoB levels.
- These patients often have what? 5
- Familial hypertriglyceridemia or type 4
- glucose intolerance
- obesity
- hyperuricemia and
- many have peripheral artery disease.
- HTN
- Familial hypertriglyceridemia or hyperlipoproteinemia type 4: Mono or polygenic?
- What level of TG do you usually see?
- what else would you see on their lipid panel?
- polygenic disorder
- moderate hyperTG (200-500mg/dL)
- low HDL-C
Familial hypertriglyceridemia or hyperlipoproteinemia type 4: what is the gene mutation?
heterozygous for inactivating mutations of the LPL gene
Familial hypertriglyceridemia or hyperlipoproteinemia type 4: they may be at risk for the development of what? and in what setting?
- chylomicronemia syndrome
- when secondary factors are present such as untreated DM or the use of TG raising drugs
Unsure if they have risk of ASCVD, recent studies suggest so.
Familial combined hyperlipidemia or hyperlipoproteinemia type 2: lipid testing shows? 4
- hypercholesterolemia,
- hypertriglyceridemia or both, and
- elevated ApoB concentration
- small, dense LDL particle
Which hyperlipoproteinemia = May present with hypercholesterolemia, hypertriglyceridemia or both, and elevated ApoB concentration with small, dense LDL particles.
Familial combined hyperlipidemia or hyperlipoproteinemia type 2
Family history of premature ASCVD is commonly seen
Familial combined hyperlipidemia or hyperlipoproteinemia type 2: is characterized by what?
poly or mono?
A polygenic disorder characterized by increased ApoB be concentration
Familial combined hyperlipidemia or hyperlipoproteinemia type 2: accounts for what percentage of Familial causes of coronary heart disease and ___% of the causes of premature CHD?
- half
2. 10%
Familial combined hyperlipidemia or hyperlipoproteinemia type 2: Depending on the phenotype, patients may exhibit increases in (1) and (2) with predominantly (3) LDL particles, hypercholesterolemia due to increased (4) or isolated (5).
The variability in phenotype is thought to relate to both the (6) and in about one third of cases, (7)
- VLDL
- LDL
- small
- LDL particle concentration
- hypertriglyceridemia
- type of LDL subclass pattern
- abnormal function of LPL
Which hyperlipoproteinemia = Characterized by marked hypertriglyceridemia with increased circulating chylomicrons and VLDL.
How does it present in adults?
Hyperlipoproteinemia type V, mixed hypertriglyceridemia
May present in adults with
- pancreatitis,
- eruptive xanthomas,
- coronary artery disease and or
- peripheral artery disease
Hyperlipoproteinemia type V, mixed hypertriglyceridemia:
poly or mono?
Characterized by?
Due to?
- Polygenetic disorder
- characterized by very high triglycerides
- due to increases in both chylomicrons and VLDL
Hyperlipoproteinemia type V, mixed hypertriglyceridemia: how do patients present?
- Abdominal pain due to acute pancreatitis,
- eruptive xanthomas,
- lipemia reanalysis and
- hepatosplenomegaly
- What is the underlying pathophysiologic abnormality in metabolic syndrome?
- This is associated with an increased concentration of what?
- What is the result of this?
- insulin resistance
- portal vein long chain free fatty acids
- The result is inhibition of hepatic ApoB degradation and increased hepatic secretion of triglyceride rich ApoB lipoprotein
Metabolic syndrome: Catalyzed by cholesterol ester transfer protein, triglycerides are transferred from (1) to both (2) and exchanged for cholesterol esters.
The presence of (3) acts to increase hepatic lipase expression on the surface of hepatocytes.
Hepatic lipase hydrolyzes triglycerides and phospholipids from LDL and HDL particles, resulting in (4).
(5) are readily eliminated by renal excretion.
These mechanism explain the findings of (6) seen in patients with metabolic syndrome.
- VLDL
- LDL and HDL particles
- long chain fatty acids
- smaller size LDL and HDL particles
- Small HDL particles
- hypertriglyceridemia, small LDL particles and low HDL C
Studies had suggested that small dense LDL particles may have the following features: 3
- May be more pro atherogenic than large LDL particles, presumably because they are better able to penetrate endothelial cell variant into the intima,
- are more susceptible to oxidation, bind to proteoglycans in the arterial wall, and
- have a longer half-time in the circulation than large LDL particles.
Extra tidbit: large LDL particles are still pro-atherogenic and found commonly in FH patients. There is no indication to test for particle size. atherogenic particle concentration (among other risk factors) is still the preferred risk assessment.
Synthesis and catabolism of high density lipoprotein particles: Its limitation with cholesterol esters is facilitated by what?
lecithin cholesterol acyl transferase (LCAT)
What is HDL composed of?
- phospholipids
- cholesterol
- a small amount of TG
- apolipoproteins
- What is the major apolipoprotein that makes up HDL?
- It is synthesized and secreted by?
- It accounts for what percentage of HDL’s protein mass?
- What accounts for the remaining percentage?
- Apo A-I
- intestines and liver
- 70%
- Apo A-II (produced exclusively by the liver)
HDL synthesis and catabolism: What does Apo A-II do and is it good or bad?
Apo A-II appears to inhibit the activity of Apo A-I and therefore is considered to be pro atherogenic lipoprotein
HDL synthesis and catabolism: What activates LCAT?
Apo A-IV
Which apolipoprotein in HDL particles promotes the uptake of remnant particles by the liver?
Apo E
HDL synthesis and catabolism: The up-regulation of and the expression of (1) in the down-regulation of (2) are potential athero-protective therapeutic targets
- Apo A1 and 4 or Apo E
2. Apo A-II
HDL catabolism and synthesis:
(1) functions as a scaffold for acquisition of phospholipids and cholesterol from lipoprotein particles. The acquisition of free cholesterol from the liver and intestines is facilitated by the (2).
Additional cholesterol is added to nascent HDL particles by the (3). The esterification of free cholesterol in HDL particles is medicated by (4) and leads to maturation of the HDL particle.
Rare mutations in the LCAT are associated with accumulation of unesterfied cholesterol in the (5), and may result in (6).
HDL particles also require lipids for metabolism of (7) via phospholipid transfer protein.
- Apo A-I
- ABCA 1 cassette binding transporter
- ABCG1 transporter and scavenger receptor B1
- lecithin cholesterol acyl transferase (LCAT)
- cornea, kidneys, and erythrocytes
- corneal opacities, chronic kidney disease and hemolytic anemia
- chylomicrons and VLDL remnants, and of phospholipids
HDL synthesis and catabolism:
The cholesterol ester from HDL particles may be taken up by the liver and steroidogenic cells through the action of the (1) or it may be exchanged for (2) via (3).
- scavenger receptor B1 (SRB1)
- triglycerides from Abo B containing particles
- cholesterol ethyl transfer protein (CETP).
HDL synthesis and catabolism:
- What does SRB1 mediate?
- Therefore, upregulating SRB1 lowers what? BUt may improve what?
- selective uptake of cholesteryl esters without the removal of apo A-I
- lowers HDL-C but may improve the circulatory availability of HDL particles.
HDL synthesis and catabolism: In the presence of hypertriglyceridemia, triglyceride enriched HDL is hydrolyzed by (1) to form (2). This metabolic effect is further enhanced by (3), a member of the lipase family but is synthesize by (4).
These very small HDL particles cannot penetrate the (5) and are excreted by their interaction with megalin and cubulin receptors in the (6).
- hepatic lipase
- smaller HDL particles
- endothelial lipase
- endothelial cells
- glomerulus
- proximal renal tubules
Add figure 1 from question 15
HDL particles exhibit multiple effects to protect against the atherosclerotic process including: 7
- reduced endothelial monocyte adhesion
- reduce monocyte chemo taxis
- enhance macrophage cholesterol and reflux
- reduced smooth muscle cell proliferation
- anti-inflammatory effects
- improved endothelial function
- reduced platelet aggregation
Potential atheroprotective activities of HDL and the development of atherosclerotic lesions. Inhibitory activities are shown and read in activating/promoting HDL activities and green. See figure.
HDL has the ability to inhibit monocyte adhesion by inhibiting
- (3 ways)
- suppresses monocyte chemotaxis by inhibiting (2) such as monocytic chemo tactic protein 1 (MCP1).
- HDL promotes cholesterol efflux from macrophage foam cells via the
- thereby preventing (4) from lipid laden macrophages.
Attach question 15 figure 2
- vascular cell adhesion molecule (ECAM–1),
- intercellular cell adhesion molecule (ICAM–1)
- E selection expression
- hemoconcentration
- cholesterol exporter ATP binding cassette transporter A1 (ABCA1, ABCG1) and scavenger receptor type SRB1.
- excessive cholesterol accumulation and the secretion of pro-inflammatory cytokines
HDL synthesis and catabolism:
HDL enters the lymphatic vessels via (1) to promote (2).
HDL inhibits (3). HDL binding to endothelial S RB1 and presenting HDL associated sphingosine–1–phosphate to endothelial S1P receptors activates (4)
- SRB 1
- reverse cholesterol transport
- smooth muscle cells proliferation and migration into the intima
- endothelial nitric oxide synthetase.
Add figure
HDL syntheis and catabolism:
In addition, HDL induces cholesterol reflux via (1) reduces inhibitory interactions of (2).
Activation of cholesterol efflux pathways by HDL via ABCA1 and ABCG 1 controls the proliferation of (3)
- ABCG 1
- endothelial nitric oxide with cavelon–1 (CAV1)
- Hematopoietic stem cells (HP SC).
Low HDL-C concentration is particularly prevalent in with ethnicity?
men with south Asian ancestry
What, like hepatic lipase, facilitates catabolism of HDL particles?
endothelial lipase