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Cardiopulmonary Renal > HDL & Lipoprotein Disorders > Flashcards

HDL & Lipoprotein Disorders Flashcards

1
Q

What is the main function of HDL?

A

To prevent or reduce atheroma

HDL is formed as an “ empty” phospholipid shell and is filled in the blood with cholesteryl esters and transfers cholesterol away from blood vessels and delivers it to the liver

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2
Q

When do HDLs transport cholesterol ?

A

They transport cholesterol back to the liver from cell membrane

Free cholesterol is component of all mammalian cell membranes in both layers. It regulates the membrane fluidity especially during temperature changes

Cholesterol ABC transporters release free cholesterol into the blood from membranes undergoing turnover and from dying cells

HDL will transport this cholesterol in form of cholesteryl esters in the reverse cholesterol transport

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3
Q

What is the function of macrophages in reverse cholesterol transport ?

A

Uptake of LDL with the LDL-receptor and uptake of oxLDL with SRs

Release of free cholesterol by the ABCA1-cholesterol transporter and other transporters fir the reverse cholesterol transport by HDL

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4
Q

How is it possible to form cholesteryl esters in the blood?

A

Free cholesterol is provided by the plasma membrane cholesterol ABCA1 transporter from peripheral tissues and macrophages

Lecithin-cholesterol acyl transferase (LCAT) is an enzyme synthesized in the liver and released into the blood . LCAT needs activation by apo A-1, binds to HDL and uses a fatty acid from phosphatidylcholine (PC) of the HDL membrane to form cholesteryl esters (CE) in the blood. CE move immediately inside the HDL.

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5
Q

How does reverse cholesterol transport uses the SR-B1 receptor?

A

HDL binds to SR-B1, opens shortly and the cholesteryl esters (CE) flow into the liver. The smaller HDL leaves and can be filled again in the blood using LCAT. LDL can contain CE from HDL and binds to LDL- receptor

CE from HDL (CETP) can reach the liver inside of LDL

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6
Q

Explain depth reverse cholesterol transport from peripheral tissues to the liver

A
  1. The nascent HDL has a disc shape and is released by liver or intestine. The HDL contains mostly phosphatidylcholine and apo lipoproteins. Apo A1 represents about 70% of the apoproteins bound in HDL and is kept by HDL in order to activate LCAT. The apolipoproteins apo E and apo C II are bound to HDL and are prov8ded in the blood to chylomicrons and VLDL. The HDL changes to a globular shapes after it is filled in the blood with cholesteryl esters
  2. The cholesteryl esters (CE) are formed in the blood by lecithin-cholesterol-acyl transferase (LCAT or PCAT). This enzyme is synthesized in hepatocytes and released into the blood where it needs activation by Apo A1. This helps to recognize HDL.
  3. The larger mature HDL binds to the hepatic scavenger receptor SR-B1 and the cholesteryl esters in HDL are equilibrated with the hepatic intracellular cholesteryl esters. The smaller HDL recirculate in blood and are filled again with cholesteryl esters
  4. Some mature HDL interact with VLDL facilitated by the protein CETP (cholesteryl esters transfer protein). Some cholesteryl esters from HDL are taken up into VLDL in exchange for TAGs and reach the liver inside of IDL & LDL.

NOTE: SR-B1 is not only found in the liver but is also found in tissues that synthesize steroid hormones . In macrophages SRB-1 is one of the transporters that release free cholesterol into the blood.

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7
Q

How can HDL cholesteryl esters reach the liver inside of IDL & LDL?

A

CETP forms a hydroph9bic channel and connects HDL and VLDL for exchange of nonpolar lipids

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8
Q

What are the hypolipedmias?

A
  1. Hypolipidemias
    a. Hypoalphalipoproteinemia: low HDL
    Hereiditary: tangier disease or acquired: often related to hypertriacylglycerolemia

b. Abetalipoproteinemia and Hypobetalipoproteinemia: low VLDL, LDL and CM. (Deficiency of MTP or apo B, similar clinical features)

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9
Q

What are the main hyperlipidemias?

A

Hyperlipidemias

a. Hypertriacylglycerolemias
Hyperlipidemia Type I, IV (common) and V.
High levels of chylomicrons (I), VLDL (IV) or both (V)

b. Hypercholesterolemias
Hyperlipidemia type IIa: high LDL(common)
Hyperlipidemia type IIb: high LDL and high VLDL (common)
Hyperlipidemia type III: high IDL, CM remnants and abnormal VLDL

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10
Q

What causes hypoolipidemias?

A

Hereditary: tangier disease (ABCA1 cholesterol transporter)

Acquired: found in patients with:
Hypertriacylglycerolemia (important dyslipidemia)
Obesity
Smoking
Medical drug treatment
Deficient LCAT
deficient apo A1
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11
Q

How are low HDL risk factors for cardiovascular disease?

A

Tangier disease: extremely low HDL levels

This rare hereditary disease is indicated by orange colored tonsils in nearly all children (orange color from cholesterol)

Common are peripheral neuropathy and premature MI (about 30%)

Macrophages are filled with cholesterol. Enlargement of liver and spleen. Sometimes corneal opacities

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12
Q

What causes tangier disease?

A

Caused by genetic defect of the cell membrane cholesterol transporter ABCA1

The deficient ABC cholesterol transporter in the plasma membrane and in macrophages leads to less free cholesterol as substrate for LCAT.

The HDLs are not sufficiently filled with cholesteryl esters wh8ch leads to degeneration of Apo A1 or the smaller HDLs. At the same time more foam cells are formed.

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13
Q

What are causes and clinical features of hypolipidemia?

A

Low chylomicron, VLDL and LDL levels

Abetalipoproteinemia (MTP deficiency)
Hypobetalipoproteinemia (apo B 48 and apo B 100 deficiency)

Both abnormalities lead to same clinical features:

  • failure to thrive. Fat metabolism with severe neonatal steatorrhea
  • TAG accumulation in epithelial cells of liver aand intestine
  • Retinitis pigmentosa, progressive blindness
  • Peripheral neuropathy (vitamin A and vitamin E)
  • Acanthocytosis (RBC with spivules)
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14
Q

What cause abetalipoproteinemia?

A

MTP deficiency

Strongly reduced release of VLDL and chylomicrons

Blood TAG levels below 19 mg/ dL
Total cholesterol below 50 mg/dL

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15
Q

What are the risk factors of cardiovascular disease?

A

Hyperlipidemias

Abnormal high levels of lipoproteins:

  1. Hypercholesterolemia (high cholesterol)
  2. hypertriacylglycerolemia (high TAG)
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16
Q

What is meant by high cholesterol in blood?

A

Cholesterol in the blood is the total cholesterol found in all lipoproteins and high cholesterol is above 200 mg/dL

Normal LDL- C= 100-130 mg/dL

Normal HDL-C= males: 50 mg/dL females: 70mg/ dL

Normal VLDL-C: 20-30 mg/dL

17
Q

What is meant by high TAGs?

A

Chylomicrons (CM) and VLDL transport most TAGs in the blood

Normal fasting TAGs are 100-150 mg/dL mostly found in VLDL. CM are normally not found in blood during fasting

An abnormal increase of CM or VLDL leads to high TAGs in blood

18
Q

What lipid levels are risk factors for cardiovascular disease?

A

Dyslipidemias

Abnormal lipoprotein pattern:

High LDL-C> 160 mg/dL

High TAG > 200 mg/dL

Low HDL -C < 40 mg/dL

19
Q

What is the primary cause of Dyslipidemia?

A

Genetic disorders with single or multiple gene mutations that can result in:

  • defective clearance or overproduction of TAG and LDL.
  • Excessive clearance or underproduction of HDL.

Often manifest when secondary causes are present

20
Q

What are the causes of secondary dyslipidemia?

A
  • smoking
  • sedentary lifestyle
  • unhealthy diet
  • diabetes
  • obesity
  • metabolic syndrome
  • alcohol overuse
  • chronic kidney damage
  • hypothyroidism
  • cholestatic liver diseases
  • HIV
  • Specific drug treatment
21
Q

Describe lipid profile for screening for CVD risk factors. What is measured and what is calculated?

A

Total cholesterol (C), HDL-C and VLDL-TAGs are routinely measured and are then used to calculate LDL-C by the Friedwald equation

LDL-C= total C-🦯[(HDL- C) + (TAG/5)] This is a Consensus statement of the America Diabetes Association & American College

Note: LDL-C includes IDL-C

VLDL-C assumption: cholesterol represents about 20% of VLDL.
HDL-C is measured after lipoproteins containing apo B are precipitated. HDL does not contain apo B are precipitated. HDL does not contain apo B

22
Q

How are hyperlipidemias grouped?

A

Can be grouped using the Fredrickson Phenotype classification (type I-V) which follows and describes the abnormal pattern of blood lipoproteins

Relative prevalence of familial forms of hyperlipoproteinemia (Type I-V)

23
Q

What is type I hyperlipidemia?

A

Familial hyperchyoomiccronemia (rare)

This is a rare disease characterized by a high serum TAG level (above 750 mg/dL) due to a high chylomicron level. Normally chylomicrons are absent in fasting serum

The patient’s blood shows in a vial lipemic plasma (milky, turbid)which after 4 hrs has a creamy layer on top.

Type I can result from the rare deficiency of lipoprotein lipase (LPL), very rare deficiency of apo C-II or other factors leading to diminished chylomicron clearance. (apo A-IV found in chylomicrons may be deficient)

24
Q

What are the clinical features of type I hyperlipidemia

A

Onset in childhood often leads to abnormal colic in infants and failure to thrive

Patients can encounter:
-lipidemia retinalis (vessels creamy white)

  • hepatosplenomegaly
  • recurrent epigastric pain with increased risk of pancreatitis at TAG levels larger than 1,000 mg/dL

Xanthomas

Characteristic are Eruptive Xanthomas which usually occur in clusters on the skin located on the trunk, buttock or extremities

25
Q

Describe type IIa hyperlipidemia

A

Familial hypercholestremia (common)

High LDL, normal VLDL and clear serum.

Risk of cardiovascular disease (CVD) and MI. Treated mostly with diet, weight loss, exercise, statins and bile acid binding drugs and fibrates.

Heterozygous FH show adult onset with total cholesterol 250-500 mg/dL
Homozygous FH is rare with high risk of childhood MI and death.

Defective LDL-receptor (autosomal dominant) or diminished clearance of LDL(apo B 100)

Often tendon Xanthomas and xanthelasma near eyelids

26
Q

Describe type IIb of hyperlipidemia

A

This is familial combined hyperlipidemia (common)

High LDL, high VLDL and lipemic, turbid serum

Risk of cardiovascular disease (CVD) and MI. Treated mostly with diet, weight loss, exercise , statins and fibrates.

It occurs often combined with smoking, diabetes, obesity, metabolic syndrome, and an unhealthy lifestyle

Heterozygote show puberty onset with total cholesterol 250-500 mg/dL and TAGs 250-750 mg/dL. Xanthomas are rare.

Complex disease which could result from multiple defects:
Overproduction of apo B 100
Overproduction of VLDL
Defective clearance of LDL

27
Q

Describe type III hyperlipidemia

A

Dysbetalipoproteinemia (rare)

High chylomicron remnants and IDL but also abnormal B-VLDL

Total cholesterol 250-500 mg/dL (IDL) and TAG 250-500 mg/dL(B-VLDL). Adult onset with accelerated atherosclerosis

The disease results from apo E deficiency. Patients lack apo E3 and are homozygous for inefficient apo E2

Often palmar Xanthomas and tubererruptive xanthomas over the elbow and knees

28
Q

Describe type IV hyperlipidemias

A

Familial hyperbetwlipoproteinemia (common)

High VLDL, normal LDL, and often low HDL

TAG 200-500 mg/dL, lipemic, turbid plasma

High VLDL level may result from LPL deficiency or VLDL overproduction. High VLDL lead to low HDL.

High serum TAGs increase the risk of pancreatitis and CVD

VLDL is also named prebetalipoprotein (electrophoresis)

29
Q

Describe type V hyperlipidemia

A

Type 5 : familial mixed hypertriacylglycerolemia

High chylomicrons and high VLDL

Disease may be caused by similar factors lead to type I or to type IV hyperlipidemia but in this case it will lead to elevated levels of both TAG-rich lipoproteins

Patient’s blood shows in a vital lipemic plasma with a turbid lower part from high VLDL and with a creamy layer on top (chylomicrons)

30
Q

How can lipoproteins be recognized?

A

By abnormal lipoprotein separation, lipoprotein electrophoresis

31
Q

What is the concept to treat hypercholesterolemia?

A

The goal is to increase hepatic LDL receptors this leads to uptake of more LDL inti the liver. And reduces blood cholesterol.

32
Q

How can an increase of LDL-R can be achieved?

A

a. stimulated LDL-R synthesis at low hepatic free cholesterol. Treatment commonly uses statin drugs that competitively inhibit HMG CoA reductase which is the regulated enzyme of cholesterol synthesis
b. Increased LDL-R recycling and decreased LDL-R degradation. Treatment with PCSK9-inhibitor drugs when statins do not work

33
Q

What is the normal function of PCSK9?

A

It leads to the degradation of the LDL-receptor.

34
Q

Explain the mechanism of PCSK9

A

This is the proprotein convertase subtilisin/kexin type 9 serine protease which prevents LDL-R recycling

PCSK9 regulates and decreases the amount of LDL-receptors found in the plasma membrane by leading to the degradation of LDL-R in lysosomes

  1. PCSK9 is a protein that is synthesized in the liver and released into the blood where it binds to some of the hepatic LDL-receptors
  2. LDL binding activates the LDL-receptor and then PCSK9 is endocytosed together with the LDL/LDL-receptor complex
  3. PCSK9 locks the LDL-receptor into a specific conformation which prevents endosome formation and the LDL-receptor is not recycled but instead degraded in lysosomes together with LDL
35
Q

How does the PCSK9-inhibitor work?

A

Two human monoclonal antibodies are approved by the FDA that bind PCSK9 in blood and render it inactive to bind to the LDL receptor

Treatment is by parenteral injection and is approved when high LDL-C cannot be controlled by statins. The drugs are injected every two weeks or monthly

36
Q

What is LDL-B?

A

Is smaller and more dense than LDL-A

Penetrates the endothelium easily

Is oxidized to ox-LDL

LDL-B pattern can result from:

  • saturated fatty acids
  • trans fatty acids
  • cleavage of TAGsbin LDL-A by hepatic lipase
37
Q

Is lipoprotein (a) A risk factor for coronary heart disease?

A

Lp(a) is very similar to LDL but it has apo(a) linked to apo B-100 by a disulfide bond

Apo(a) is a structural analog to plasminogen and may compete for the bind8ng to fibrin. As a result: Lp(a) may reduce the removal of blood clots which could trigger MI or stroke

38
Q

How do oxLDLs lead to coronary heart disease?

A

oxLDLs which enter macrophages via the scavenger receptor SR-A lead to foam cells. High levels of LDL-B which are small, easily trapped and oxidized. Lp(a) which may reduce the blood clot removal

39
Q

Explain drugs being used to treat hypercholesterolemia

A
  1. Plant sterols and Stan old can be added to margarine and compete with the dietary uptake of cholesterol and reduce it.
  2. The drug Ezetimbe inhibits a specific intestinal cholesterol transporter
  3. Bile acid binding drugs (Cholestyramine) reduce the re-uptake of bile acids in the terminal ileum and the liver uses free cholesterol to synthesize bile acids. This leads to hepatic LDL-R synthesis as the cytosolic free cholesterol levels is lower than normal
  4. Partial ileal bypass reduces re-uptake of bile acids and increases hepatic bile acid synthesis. This leads to hepatic LDL-R synthesis similar to treatment with cholestyramine
  5. Inhibition of hepatic cholesterol synthesis by statin drugs. Statins are competitive inhibitors of HMG-CoA reductase which is the regulated enzyme of cholesterol synthesis
  6. PCSK9 inhibitors lead to increased recycling of the hepatic LDL receptors. This increases the amount of LDL receptors by reducing LDL-R degradation in hepatocytes

Cardiopulmonary Renal (35 decks)

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