Chapter 27 Dyslipidemia Flashcards
Corneal arcus, tendinous xanthomas, and xanthelasmas are common
Familial hypercholesterolemia (FH)
- low density lipoprotein receptor
Clinically indistinguishable with Familial defective apolipoprotein B
> An autosomal co-dominant disorder that results from defects in the LDL receptor gene (low-density LDL receptor)
LDL levels greater than the 95th percentile for age and gender
Familial hypercholesterolemia (FH)
Men with heterozygous FH usually develop coronary artery disease (CAD) by the third or fourth decade. Affected women present 8 to 10 years later.
> cardiovascular risk greater than 10-20x
a young patient with eruptive xanthomas
* plasma triglyceride level of 22 mmol/L (2,000 mg/dL)
* as a result of LPL deficiency or other monogenic defects
Clinical definition of familial hypercholesterolemia
combining LDL-C, family history of elevated
cholesterol, or premature ASCVD
oThese definitions are highly concordant and rely on
-absolute levels of LDL-C (>330 mg/dL)
-family history of premature ASCVD,
-family history of elevated LDL-C,
-cutaneous manifestations
-if available, DNA analysis.
Corneal arcus, tendinous xanthomas, and xanthelasmas are common, resulting from mutations in the APOB gene.
>results in a reduced affinity of affected LDL particles for the LDL receptor.
Familial defective apolipoprotein B
> polygenic condition with abnormalities that include elevations of LDL and/or triglycerides, a reduction in HDL, and elevated apo B levels
increased risk of CAD, and there can be considerable clinical overlap with the insulin-resistance metabolic syndrome.
Physical findings such as corneal arcus or xanthomas are rare.
Familial combined hyperlipidemia (FCH)
> polygenic disorder characterized by elevated triglycerides with normal or low LDL levels and reduced HDL
Do not develop xanthomas or xanthelasmas
high propensity to develop CAD
Familial hypertriglyceridemia (type IV hyperlipoproteinemia)
> Gain-of-function mutations in this gene decrease the availability of the LDL receptor, which causes higher plasma LDL cholesterol
increased risk of ischemic heart disease
proprotein convertase subtilisin/kexin type 9 gene (PCSK9)
>encodes a protease that binds to the LDL receptor and targets it for lysosomal degradation.
disorder is characterized by premature atherosclerosis and is notable for both hypercholesterolemia and hypertriglyceridemia owing to an increase in IDL and/ or VLDL particle populations
dysbetalipoproteinemia or broad beta disease
type III hyperlipoproteinemia
> an omega-3 fatty acid studied in
REDUCE-IT trial with a large, randomized trial of 8179 patients with established cardiovascular disease, or diabetes plus additional risk factors, who manifested hypertriglyceridemia (135–499 mg/dL) despite statin therapy
Over the subsequent 4.9 years, the patients randomized to this drug experienced a 25% lower risk of major adverse cardiovascular events compared with the placebo group
eicosapentanoic acid derivative, 2 g twice daily
Agents that interact with a nuclear transcription factor (PPAR-alpha) that regulates the transcription of the lipoprotein lipase, APOCII, and APOAI genes
> may cause low-density lipoprotein (LDL) levels to rise
Fibric acid derivatives (e.g., gemfibrozil, fenofibrate)
Selectively inhibits cholesterol uptake by intestinal epithelial cells and reduces LDL cholesterol when used alone or in combination with statins
ezetimibe
Tuberous xanthomas
Palmar striated xanthomas
Type III hyperlipoproteinemia
aka
Dysbetalipoproteinemia
What do LDL particles predominantly contain?
Cholesteryl esters packaged with apo B100
LDL particles normally have only 4% to 8% triglycerides in their mass.
What happens to LDL particles in conditions with elevated plasma triglyceride concentrations?
They acquire triglycerides and deplete their core cholesteryl esters
This results in smaller, denser LDL particles.
How do humans differ from other mammals regarding LDL?
Humans generate LDL as a cholesterol-rich lipoprotein
Nonhuman primates can also carry cholesterol in LDL when fed a cholesterol-enriched diet.
What is the primary mechanism by which cells internalize LDL?
Via LDL-R
The LDL-R binds to LDL particles and localizes in a region of the plasma membrane rich in clathrin.
What role does clathrin play in the internalization of LDL?
Clathrin polymerizes and forms an endosome containing LDL and its receptor
This endosome then fuses with lysosomes for further processing.
What enzyme is involved in the degradation of apo B within lysosomes?
Cholesteryl ester hydrolase
Other enzymes like cathepsins also participate in this process.
What is the function of PCSK9 in relation to LDL-R?
PCSK9 binds to LDL-R and diverts it to the lysosomal degradative pathway
This prevents the recycling of LDL-R back to the plasma membrane.
What genetic mutations are associated with PCSK9 and cholesterol levels?
Gain-of-function mutations cause autosomal dominant hypercholesterolemia, whereas loss-of-function mutations increase LDL-R and lower LDL-C
This illustrates the role of PCSK9 in cholesterol regulation.
List the four pathways through which cells regulate their cholesterol content.
- Synthesis of cholesterol in the smooth endoplasmic reticulum
- Receptor-mediated endocytosis of LDL
- Efflux of cholesterol to acceptor particles
- Intracellular cholesterol esterification via ACAT
These pathways are tightly regulated and involve various proteins and enzymes.
What is the rate-limiting step in cholesterol synthesis?
Hydroxymethylglutaryl-CoA (HMG-CoA) reductase
This step occurs in the smooth endoplasmic reticulum.
What is the role of SREBP-2 in cholesterol regulation?
SREBP-2 coordinates the regulation of cholesterol synthesis and receptor-mediated endocytosis of LDL
It does this at the level of gene transcription.
Name the disease:
Extreme elevation in the plasma TAG (>10,000 mg/dl)
Recurrent pancreatitis
Eruptive xanthomas
Monogenic chylomicronemia
