T14 - Disorders of TG Metabolism Flashcards
How are exogenously-derived ApoB-containing lipoproteins produced?
incorporation of dietary lipids into chylomicrons, which occurs in enterocytes
How are endogenously-derived ApoB-containing lipoproteins produced?
incorporation of liver lipids into VLDL
List the four major parallels of the exogenously-derived lipid and endogenously-derived lipid metabolism pathways.
formation of TG-rich particles (ApoB-48 in chylomicrons, ApoB-100 in VLDL)
both CMs and VLDLs acquire ApoE and ApoC
CMs and VLDLs both become cholesterol rich as TGs are unloaded into periphery
CMs and VLDLs both become remnants which are cleared from circulation by hepatic LDLR endocytosis
Describe the characteristics of a venous blood sample obtained from a fasting individual.
all CMs and CMrs have been cleared from circulation
VLDLr levels low
cholesterol in blood is exclusively in LDL and HDL, with smaller amounts in VLDL
Describe the steps of the most ocmmon test used to determine lipoprotein-cholesterol levels. (4)
venous blood sample obtained from fasting individual
plasma separated from blood cells via centrifugation
supernatant collected and TG + total cholesterol measured enzymatically
remaining ApoB-containing lipoproteins (VLDL, IDL, LDL) precipitated and remaining cholesterol that is measured is bound to HDL
HDL cholesterol can be measured directly from a lipid profile. How is VLDL cholesterol measured? What are the assumptions underlying this measurement?
it is estimated by dividing fasting TG level by 5
assumption is that all TG in a fasting sample is carried in VLDL
What is the equation to calculate LDL-cholesterol?
total cholesterol = VLDL-C + LDL-C + HDL-C
LDL-C = total cholesterol — (total TG/5 + HDL-C)
What criteria must be met for the LDL-C calculation to be considered accurate? (3)
fasting subject, so no CMs or CMRs present
TG is <300 mg/dL
person does not have Type 3 hyperlipoproteinemia
What is a normal plasma total cholesterol value?
120-200 mg/dL
What is a normal plasma total triglyceride value?
50-200 mg/dL
What is a normal plasma HDL cholesterol value?
35-80 mg/dL
What is a normal plasma LDL cholesterol value?
70-160 mg/dL
What is hypertriglyceridemia?
abnormal elevations of CMs or VLDLs [remember that triglyercides constitute the bulk of these particles] (with the exception of Type 3 hyperlipoproteinemia)
What is the major lipid carrie din LDL and HDL?
cholesterol
What fraction of plasma cholesterol is carried in LDL?
70%
What factors can contribute to combined hyperlipidemia (i.e. elevations in both TG and cholesterol)? (3)
increased remnants
elevated LDL + VLDL
elevated VLDL + chylomicrons
What is another name for hypertriglyceridemia?
chylomicronemia
What are the TG levels in a patient with chylomicronemia?
fasting TG: >700 mg/dL
normal TG: >1000 mg/dL
How does plasma appear in a patient with chylomicronemia?
milky-cloudy-“strawberry milk” appearance, because the large CM and VLDL particles are scattering light
Explain why a blood sample with excess CM refridgerated overnight will have a layer of “cream” the next morning.
CM and VLDL have a lower density than the plasma density, so they will float to the top
What is the clinical presentation of eruptive xanthomas?
nontender yellowish papules (little bumps) full of TG appear on extensor surfaces of arms and legs at pressure points
What is the underlying cause of eruptive xanthomas? How long do symptoms last?
caused by collection of TG-filled macrophages in the skin
appear suddenly and regress with resolution of chylomicronemia
Describe the clinical presentation of lipemia retinalis.
arteries in eye discolored on fundoscopic examination
instead of bright red blood, contains “strawberry milk” or “tomato soup”
When does lipemia retinalis occur?
when TG exceeds 4000 mg/dL
(T/F) Patients with lipemia retinalis suffer from vision loss.
False. Patients with lipemia retinalis do not have any visual problems.
What happens in pancreatitis? (2)
CMs accumulate in capillaries of pancreas and destroy it
digestive enzymes enter abdominal cavity and digest tissue
Prolonged chylomicronemia can result in enlargement of what two organs?
liver (hepatomegaly) and spleen (splenomegaly), because of uptake of CMs by nonspecific pathways
Chylomicronemia is specifically NOT associated with what condition?
chylomicronemia is NOT associated with an increase in coronary atherosclerosis
What are the four major diseases associated with chylomicronemia?
eruptive xanthomas
lipemia retinalis
pancreatitis
enlargement of liver/spleen
What is lipoprotein lipase deficiency and what is its inheritance pattern?
rare autosomal recessive disorder due to inactivating mutations in LPL gene
When does lipoprotein lipase deficiency present, and how? (3)
usually presents in infancy/childhood w/ failure to thrive and recurrent abdominal pain due to pancreatitis, soemtimes + eruptive xanthomas
How is LPL activity measured? (6)
heparin injected into blood
heparin displaces LPL from GPIHBP1
LPL and hepatic lipase accumulate in circulation
incubate with TG to measure total lipase activity
add antibody to inactivate HL to all lipase activity is coming from LPL
incubate again w/ TGs and measure the amount of free fatty acids that come out
How is LPL deficiency treated? (4)
patient is hospitalized and not allowed to eat or drink anything to stop new CM formation
IV fluids provided until TGs are <700 mg/dL
initiate low fat diet (<20 g fat/day) to minimize CMs entering circulation
levels of TG will gradually fall as CMs are slowly + non-specifically taken up by macrophages in spleen and liver
Explain why a homogzygous loss of ApoCII functionality leads to chylomicronemia.
ApoCII required for CM to interact with LPL and digest TGs
therefore, TG levels rise
How does ApoCII deficiency present clinically?
recurrent abdominal pain
chylomicronemia
no post-heparin LPL activity
How is ApoCII deficiency treated?
whole blood transfusion — donor will have normal/functional ApoCII
What is the difference between ApoCII deficiency and LPL deficiency in terms of patient care?
ApoCII deficiency can be treated with a plasma transfusion
But LPL deficiency is a genetic problem that can’t exactly be cured
Describe the relationship between ApoCIII (not to be confused with ApoCII) and plasma TG levels.
unlike ApoCII deficiency (which causes increased plasma TG levels), mutations that inactivate ApoCIII result in lower plasma TG levels
Describe the relationship between ApoCIII (not to be confused with ApoCII) and LPL activity.
Normally, ApoCIII inhibits LPL activity
Write out the pathway of normal metabolism of VLDL (i.e. endogenous metabolism). (4)
ApoB-100 + TG + cholesterol = VLDL that is secreted into circulation → acquires ApoE and ApoC series → interacts with LPL which hydrolyzes its TGs and becomes an IDL, losing ApoC series → ApoE binds to LDLR of liver and causes endocytosis
How does Type III hyperlipoproteinemia develop?
Type III hyperlipoproteinemia develops when clearance of CM and VLDL remnants is delayed
What is the underlying cause of Type III hyperlipoproteinemia?
sequence variations in ApoE that interfere with binding to LDLR
What are the three isoforms of ApoE? List their relative prevalence.
ApoE2 (least common isoform)
ApoE3 (most common isoform)
ApoE4 (second most common isoform)
How does ApoE2, the least common isoform, differ from ApoE3 or ApoE4?
ApoE2 binds with lower affinity than either ApoE3 or ApoE4 to the LDLR
Having the ApoE2 is a predisposition to what disease?
Type III hyperlipoproteinemia. Being homozygous (ApoE2/ApoE2) is necessary but not sufficient to develop Type III hyperlipoproteinemia
ApoE2 homozygosity is a risk factor but is not sufficient to induce familial type III hyperlipoproteinemia. What further increases the probability of developing familial type III hyperlipoproteinemia?
first hit = ApoE2/ApoE2 homozygosity
second hit = increase in production of TG-rich lipoproteins (via high-fat diet, obesity, diabetes, etc.) or decrease in rate of clearance of remnants by LDLR (via high cholesterol downregulation, hypothyroidism, low estrogen)
When do the symptoms of Type III hyperlipoproteinemia become apparent?
in adulthood
What three diseases/events does type III hyperlipoproteinemia eventually cause in adults?
coronary artery disease (atherosclerosis in arteries supplying heart)
peripheral vascular disease (atherosclerosis in vasculature to extremities)
cerebrovascular disease/stroke (atherosclerosis in arteries to brain)
basically, atherosclerosis
What is xanthelasma?
accumulation of cholesteryl esters in skin around eyes
What are tuberous/tuberoeruptive xanthomas?
bumps that appear at areas of pressure (elbows, ankle, hands) that are large and red
What is striae palmaris? (2)
xanthomas of palmar creases in hand
palmar creases appear orange
Are patients with type III hyperlipoproteinemia predisposed to pancreatitis?
No. These patients do not get pancreatitis.
In terms of plasma concentrations, what is a hallmark of familial type III hyperlipoproteinemia?
cholesterol and TGs are elevated to approximately the same level (i.e. cholesterol @ 500, TGs @ 550)
How is a diagnosis of familial type III hyperlipoproteinemia made?
made by a test that measures amounts of remnants in the plasma
What are the six possible treamtnets for familial type III hyperlipoproteinemia?
low fat diet (reduce CM/CMr production)
low-cholesterol diet (increase LDLR expression)
statins to increase hepatic LDLR expression
ezetimibe to block cholesterol absorption
weight loss (reduce VLDL production)
fibric acids to reduce production/increase metabolism of VLDLs
Where on ApoB is the LDL receptor-binding domain?
on the C-terminus (therefore not present in ApoB-48)
Compare the relative sizes of ApoE and ApoB.
ApoE (48 kDa) is much smaller than ApoB (~500 kDa)
Give two examples of tissues that express high numbers of LDL receptors.
adrenal glands
gonads
[they need the cholesterol to synthesize hormones]
(T/F) LDL levels in a normal individual change significantly between the fed and fasting states.
False. LDL levels do NOT change significantly.
What is the relationsihp between CETP and HDL?
CETP deficiency leads to HDL elevation
What is the target of ezetimibe?
the NPC1L1 transporter, which absorbs cholesterol into enterocytes
What is the clinical presentation of a patient with no functional GPIHB1?
chylomicronemia (extremely high TG content)
How is the metabolism of chylomicrons and VLDL similar and how are they different?
similar: both digested by LPL, but VLDLs have a further metabolism step by hepatic lipase
different: ApoB-48 vs. ApoB-100
What ApoB-containing lipoprotein do you think would accumulate in individuals with no functional hepatic lipase?
IDLs would accumulate because IDLs use hepatic lipase as a secondary metabolism enzyme
