Module 1: Deck 4/Cards 21-33 Flashcards

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1
Q

What is the role of liver X receptor (LXR) in cholesterol homeostasis?

A

It enhances cellular cholesterol reflux via induction of ABCG 5 and ABCG 8

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2
Q

What is the liver X receptor (LXR)?

A

Is an activated nuclear receptor that, after binding with the heterodimer, retinoid X receptor, acts in concert with coactivators and co-repressors like fatty acids, oxysterols and bile acids to maintain cholesterol homeostasis

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3
Q

Liver X receptor (LXR) acts as ?

A

ligand activated nuclear recpetors that act as cholesterol sensors

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4
Q

SREBP are activated by what?

LXR are activated by what?

A
  1. low cellular cholesterol levels

2. high cholesterol levels

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5
Q

While the (1) is the target of the SREBP2 pathway, resulting in clearance of LDL particles from the circulation, LXR negatively regulates the (2), thus providing a second mechanism for feedback regulation of intracellular cholesterol levels.

As an adaptive mechanism to lower intracellular cholesterol levels, LXR’s do what? 3 for 3

L XR does have multiple other metabolic effects, some of which include? 3 for 4

A
  1. LDL receptor
  2. LDL receptor pathway
    • increase the conversion of cholesterol to bile acids,
    • enhance reverse cholesterol transport and
    • decrease small intestinal cholesterol absorption
    • increased lipogenesis
    • increase adipose tissue glucose uptake and
    • increased adipose tissue fatty acid oxidation
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6
Q

What are ABCG5/ABCG8? and where are they expressed?

Thus, defects in these genes are associated with what?

B-sitosterolemia (also known as phytosterolemia) is an extremely rare disorder due to homozygous or compound heterozygous mutations in ?

A
  1. are proteins expressed in the liver and small intestine and facilitate excretion of absorbed plant sterols and cholesterol into the intestinal lumen and bile.
  2. markedly elevated plasma levels of plant sterols (e.g. sitosterol and campesterol) and normal to moderately elevated plasma levels of cholesterol.
  3. either one of these two adenosine triphosphate binding cassette transporter genes.
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7
Q

What is farnesoid X receptor or FXR? Where is it expressed?

A

It is a nuclear bile acid receptor expressed in the

liver
kidney
intestine
adrenal glands

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8
Q

High levels of bile acids are toxic to cells. What is a nuclear receptor that plays a major role in regulating bile acid synthesis and in its modification before it is released to the gallbladder.

A

F XR

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9
Q

FXR:
1. It also affects hepatic absorption and uptake of bile acids. FXR reduces conversion of bile to cholesterol acids by what?

  1. It reduces bile acid toxicity in the liver by what?
  2. In the intestine, FXR reduces bile acid absorption how? 3 for 3
  3. FXR reduces hepatic uptake of bile acids how?
  4. In the liver it reduces what via the down-regulation of phophoenolpyruvate carboxykinase and glucose-6-phosphatase, two key enzymes involved in the glucose synthesis pathway.
A
  1. down regulating expression of enzymes involved in bile acid synthesis
  2. increasing of the bile acid modifying enzymes
  3. via down-regulation intestinal bile acid transporter,
  4. promotes bile acid movement across the enterosite via ileal bile acid binding protein and
  5. promotes recycling of bile acids to the liver.
  6. by reducing the expression of organic and ion transporting polypeptide and sodium taurocholate co-transporting polypeptide
  7. gluconeogenesis
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10
Q

FXR reduced lipogensis via inhibition of what?

A

sterol-regulatory element-binding protein 1C and fatty acid synthase.

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11
Q

FXR reduced gluconeogensis via the down regulation of what two key enzymes involved in the glucose synthesis pathway?

A

phophoenolpyruvate carboxykinase and glucose-6-phosphatase

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12
Q
  1. The 2016 American College of cardiology expert consensus decision pathway on the role of non-statin therapies for LDL cholesterol lowering in the management of atherosclerotic cardiovascular disease advises against the use of bile acid sequestrants in which patients?

Bile salts, as FXR ligands, decreased what?

Bile acid sequestrants, by inhibiting what, act as FXR antagonists, a possible explanation further triglyceride raising properties?

A
  1. patients who may require additional LDL lowering but have plasma triglycerides over 300.
  2. circulating triglycerides.
  3. bile acid reabsorption
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13
Q
  1. FXR decreases what? 4

2. It increases what? 1

A
1. 
gluconeogenesis
hepatocyte bile acid synthesis
lipogenesis
intestinal reabsorption of bile acids.
  1. increases hepatocyte bile acid modification and secretion
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14
Q

Add graphic

The left hand of a 5-year-old boy referred to lipid clinic as shown. His labs were: Total cholesterol 800, HDL 60, TG 90, and LDL 722. He was followed by lipid specialist and treated with multiple LDL lowering drugs. He developed angina in his mid teens and underwent multivessel PCI at age 19 because of worsening angina. Mutation in the gene encoding for what is the most likely–common cause of his clinical presentation?

A

LDL-receptor

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15
Q

1-4: Homozygous familial hypercholesterolemia, is an (1) genetic disorder most often caused by mutations in the gene encoding for the (2). The most common mutations of the LDL receptor occur in (3) resulting in the (4) and, therefore, the inability to properly clear LDL particles.

  1. Other mutations of the LDL receptor include what? 2
A
  1. autosomal dominant
  2. LDL receptor
  3. the binding domain
  4. uncoiling of the receptor
    • the inability to migrate to the cell surface and
    • an abnormality of the epidermal growth factor region, thereby preventing the receptor from functioning at the cell surface.
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16
Q

HoFH: Other genetic disorders that may cause a similar clinical presentation, but occur with lower frequency, include mutations in what? 4

A
  1. Apo-B 100,
  2. gain of function mutations in PCSK9,
  3. mutations in LDL related protein (autosomal recessive hypercholesterolemia) and
  4. sitosterolemia
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17
Q

What is sitosterolemia?

A

an autosomal recessive disorder in either ABCG5 or ABCG8, which impairs the function of the small intestinal sterol efflux transporter.

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18
Q

Patients with homozygous familial hypercholesterolemia accumulate LDL-C where? 3

They are at risk for? when?

The diagnosis is typically based upon the findings of what? 4

A
  1. plasma
    tendons
    skin
  2. premature ASCVD, often within the first 2 decades of life.
    • xanthomas in patients under the age of 10 years associated with
    • an untreated LDL cholesterol of over 500
    • treated LDL cholesterol of over 300 or
    • a non-HDL cholesterol of over 330.
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19
Q

What finding is pathognomic for HoFH?

A

Interdigital xanthomas, particularly between the thumb and index finger

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20
Q

HoFH: Except in parents with autosomal recessive hypercholesterolemia, parents of such patients are often homo or heterozygous?

A

heterozygous, or rarely homozygous for familial hypercholesterolemia.

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21
Q

Although homozygosity for defective alleles at the LDL receptor is very unlikely, compound genetic states characterized by different defects of the LDL receptor on the 2 receptor genes, or a mixed heterozygous state in which defects of the LDL receptor coexist with other defects such as what may be present? 2

The likelihood that 2 similar mutations are present increases greatly in the presence of consanguinity of the parents. Clustering of homozygous FH patients in certain ethnic groups, including which who is likely related to inter marriage among these ethnic groups? 4

More than 1600 mutations of the LDR receptor have been described in new mutations continue to be identified.

A
  1. Apo-B 100 mutation or
    PCSK9 gain of function mutation
2. 
French Canadians
Dutch Afrikaners in South Africa
Maronite Christians from Lebanon 
Ashkenazi Jew's from Lithuania
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22
Q

A systolic murmur is noted in a patient wit HoFH. An ECG is performed and the tracing is shown. (1 what does the tracing show?)

  1. the mostly likely cause of the patients heart murmur is ?
A
  1. LVH with secondary repolarization abnormality

2. Valvular or supravalvular aortic stenosis.

23
Q

What is the most accurate estimate for the current prevalence of familial hypercholesterolemia (FH) in the united states population?

A

1:250

24
Q

When is the LDL-C lowering response to statins especially blunted or absent?

A

LDL receptor negative HoFH

25
Q

What is the LDL-C goal for patients with FH? (1)

This is followed by achieving an LDL-C level of less than (2) which is the threshold for intensifying statin therapy or adding nonstatin drug.

A
  1. reduction in LDL-C by a minimum of 50%.

2. 100mg/dL.

26
Q

How do statins work in receptor negative HoFH patients?

What may be useful as an adjunctive therapy for these patients? why?

A

By reducing the availability of cholesterol required to form apo B containing lipoproteins and by increasing any available LDL receptor activity and those who are receptor defective.

Ezetimibe because it is not necessarily dependant on LDL receptor activity for its LDL-C lowering activity.

27
Q

How does PCSK9 work in the LDL receptor pathway?

A

After receptor mediated endocytosis, the endosomes deliver both the LDL receptor and PCSK9 into the cell.

28
Q

How many times is each LDL receptor recycled to the surface?

A

100-150 times

29
Q
  1. Genetic variants associated with (1) cholesterol levels via reduction in cholesterol absorption (NPC1L1) have a (2) risk of type 2 diabetes.

Genetic variants associated with (3) cholesterol levels via reduced endogenous cholesterol synthesis HMG CR have (4) risk of type 2 diabetes

Patients with FH have a (5) prevalence of type 2 diabetes.

A
  1. lower
  2. higher
  3. lower
  4. higher
  5. lower
30
Q

Why genetically screen individuals with LDL-C over 190mg/dL?

A

a major advantage of performing genetic testing is that it defines a group of individuals who have had a higher lifetime exposure to atherogenic LDL particles.

31
Q

Genetic variants associated with lower cholesterol levels via internalization of LDL particles into cells (PCSK9) have a higher or lower risk of type 2 diabetes.?

A

high

32
Q

Describe the pathophysiologic mechanism of lipoprotein (a)? 3

A

It binds inflammatory oxidized phospholipids and is a preferential carrier of these phospholipids in the plasma.

Additionally it carries lipoprotein phospholipase A2, which Cleaves oxidized phospholipids into short chain fatty acids and lysolecithin, further promoting monocyte adhesion

Lp(a) Also prevents clot lysis. The prothrombotic activity of LP(a) may also be related to its inhibition of the tissue factor pathway. Atherogenesis is accelerated due to intimal deposition of LP(a) cholesterol or both.

33
Q

What is the composition of Lp(a)?

A

Lp(a) is a plasma lipoprotein that is compromised of cholesterol rich LDL particle that contains 1 molecule of apolipoprotein B 100 attached via a disulfide bond to an additional protein, apolipoprotein a.

34
Q

The production rate of LP(a) as determined by what?

A

By the size of apolipoprotein a which can vary from 2 75-800 Kd.

35
Q

Individuals with high molecular weight apo a have a (1) production rate and (2) plasma LP(a) levels. In addition, the formation and secretion of (3) also plays an important role in determining plasma LP(a) levels.

A
  1. decreased
  2. lower
  3. VLDL
36
Q

Drugs that decrease VLDL formation, such as the mipomersen or lomitapide, (1) plasma LP(a) levels. The mechanism of clearance of LP(a) from the circulation is not well understood. The LDL receptor does not appear to be a major factor and drugs that increase hepatic LDL receptor level, such as statins and ezetimibe, do not lower plasma LP(a) levels

A
  1. decreased

2.

37
Q

What comorbid condition increases Lp(a) levels due to decreased clearance?

A

LP(a) binds to the Meglin receptor, which is highly expressed in the kidney. In patients with renal disease the clearance of LP(a) is decreased leading to elevated plasma LP(a) levels.

38
Q

Cholesterol absorption efficiency and cholesterol synthesis are inversely related, and they can reliably be predicted by what?

A

serum cholestatic levels.

39
Q

What correlates with whole body cholesterol synthesis?

A

lathosterol

40
Q
  1. In humans cholesterol absorption and synthesis are related how?

This relationship may be regulated by (2) which is activated by cellular oxysterol levels. LXR activation increases expression of ATP binding cassette transporter (3) resulting in decreased intestinal cholesterol absorption, thereby increasing cholesterol return to the liver

A
  1. inversely
  2. LXR
  3. ABCG5 and ABCG8
41
Q
  1. Why do statins increase intestinal cholesterol absorption?
  2. How is this different in metabolic syndrome patients and obese patients?
A
  1. Statins decrease cholesterol synthesis, thereby decreasing LXR activation, and this may explain why statins appear to increase intestinal cholesterol absorption.
  2. Paradoxically, patients with obesity and metabolic syndrome are generally low cholesterol observers with increased cholesterol synthesis.
42
Q

The NPC1L1 protein is highly expressed in the (1) and selectively absorbs both (2). That is the reason that ezetimibe which inhibits NPC 1 L1, decreases both cholesterol and plan sterol absorption.

A
  1. jejunum

2. cholesterol and plants sterols

43
Q

What is familial hypobetalipoproteinemia (FHBL)?

A

which is an autosomal dominant condition defined by LDL-C levels lower than 75 and ApoB levels below 50 with no underlying lifestyle (vegan/malnutrition) or medical (hyperthyroidism/chronic liver disease) cause.

44
Q

What is often the most common presentation for FHBL?

A

The most common presentation for this is hepatic steatosis and mild transaminase elevation.

45
Q

FHBL can put you at risk for?

A

cirrhosis or hepatocellular carcinoma which are uncommonly reported but if liver enzymes are elevated, liver imaging should be considered

46
Q

FHBL:

  1. What are plasma apoB levels like in these patients?
  2. What is the result of this? 4
A
  1. In these patients, plasma ApoB levels are about one quarter of normal.
  2. The results is that
    - hepatic secretion of ApoB 100 is about three quarters of normal,
    - there is increased catabolic some of VLDL,
    - decreased production of LDL Apo B-100 and
    - decrease triglyceride export from the liver.
47
Q

Hypolipidemia disorders:

1. Loss of function PCSK9 result in what?

A
  1. Decreased degradation of the LDL receptor and a 30 to 70% reduction in circulating LDL-C levels. Individuals with these mutations are asymptomatic and have a decreased risk of cardiovascular disease.
48
Q

What is familial combined hypolipidemia?

A

A disorder associated with loss of function mutations of AN GPT L3, a protein that inhibits lipoprotein lipase and endothelial lipase, resulting in enhanced catabolism of VLDL and HDL respectively, and low levels of LDL and HDL.

49
Q

Abetalipoproteinemia is a disorder characterized by what?

A

A rare autosomal recessive disorder characterized by very low concentrations of cholesterol and triglycerides and undetectable levels of APO B and LDL.

50
Q

Abetalipoproteinemia: This disorder is due to loss of function mutations of the gene encoding for (1), which categorizes the transfer of triglycerides to nascent APO B particles in the endoplasmic reticulum

Due to impaired assembly of VLDL particles, there is decreased (2), resulting in increased accumulation of (3) in liver cells and hepatic steatosis.

A
  1. microsomal triglyceride transfer protein (MTTP)
  2. hepatic triglyceride secretion
  3. triglycerides
51
Q

Abetalipoproteinemia: Vitamin E deficiency may result in neurologic disorders with what? 4

These patients should be recognized as early as possible and treated with what? 3

A
  1. progressive degeneration of the central nervous system,
  2. retinitis pigmentosa,
  3. spinocerebellar degeneration with ataxia,
  4. bleeding diathesis and death
  5. a low-fat diet,
  6. high doses of oral fat-soluble vitamins A and E, and
  7. supplementation with essential fatty acids
52
Q

What does MTTP do?

A

categorizes the transfer of triglycerides to nascent APO B particles in the endoplasmic reticulum

53
Q

Abetalipoproteinemia: These patients present in the first or second decade of life with what? 5

A
  1. oral fat intolerance,
  2. steatorrhea,
  3. diarrhea,
  4. failure to thrive and
  5. deficiency of fat soluble vitamin a and E.
54
Q

Lipid metabolism with mutations figure

A

figure 1