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CV Module > Lipoprotein Pathophys > Flashcards

Lipoprotein Pathophys Flashcards

1
Q

What is the preferred direction of transport for triglycerides (TGs)?

A

From the gut (intestine) and liver (where they are absorbed/manufactured) to the muscle (energy use) and fat tissue (storage).

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2
Q

What is the preferred direction of transport for cholesterol?

A

From all other tissues back to the liver.

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3
Q

What abnormality results from genetic truncations of ApoB synthesis?

A

Hypobetalipoproteinemia (a relatively common abnormality).

the resulting ApoBs are much shorter than normal

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4
Q

In hypobetalipoproteinemia, what happens to the secretion rate and clearance rate of the truncated ApoB particles?

A

They are typically secreted at a REDUCED rate, while their clearance is usually FASTER than normal.

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5
Q

How do the LDL-C levels of heterozygotes for truncated ApoB compare to that of normal people? What symptoms do heterozygotes have?

A

HETEROZYGOTES have LDL-C levels 25-50% of normal (b/c half of their VLDL apoB are normal apoB-100). They are ASYMPTOMATIC.

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6
Q

Due to their inability to secrete triglycerides from the liver, heterozygotes for truncated apoB will develop what?

A

increased fat in the liver and some may develop STEATO-HEPATITIS (fatty liver)

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7
Q

Homozygotes for hypobetalipoproteinemia will have extremely low levels of what? What will they present with? What is the presentation of abetalipoproteinemia?

A

Extremely low levels of apoB-containing lipoproteins; frequently present with FAT MALABSORPTION and NEUROMUSCULAR DEGENERATION.
Abeta has the same presentation but symptoms are worse.

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8
Q

In these homozygotes, what does fat malabsorption cause? What causes neuromuscular degeneration?

A

Fat Malabs causes FAT-SOLUBLE VITAMIN DEFICIENCY.

Neuromuscular degeneration is caused by a deficiency of Vitamin E.

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9
Q

In homozygotes for hypobetalipoproteinemia, why is there a relative deficiency of truncated apoB vs apoB-100 in LDL?

A

The RENAL TUBULE rapidly clears the VLDL containing truncated apoB.

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10
Q

What causes ABETALIPOPROTEINEMIA?

A

An absolute deficiency of “Microsomal Triglyceride Transfer Protein” aka MTP.

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11
Q

What are the two functions of MTP (microsomal triglyceride transfer protein)?

A
  1. It’s responsible for transporting triglycerides and cholesterol esters b/t phospholipid surfaces (membranes and lipoproteins).
  2. It controls the formation of a lipid droplet to which apoB can attach.
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12
Q

Is Abetalipoproteinemia a recessive or dominant trait?

A

RECESSIVE. Homozygotes have no functional MTP and can’t assemble any CM or VLDL particles. (heterozygotes appear to make enough MTP to transport adequate quantities of lipid for CM and VLDL synthesis)

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13
Q

What are two VERY IMPORTANT genetic conditions that appear to result in EXCESSIVE apoB synthesis in the liver?

A
  1. Familial Combined Hyperlipidemia (FCHL)

2. HyperapoBetalipoproteinemia

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14
Q

How are they defined? What does this mean?

A

They are both currently defined CLINICALLY, and as such, are NOT mutually exclusive. In fact, pt’s with FCHL often have Hyperabeta (not always).

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15
Q

What explains the frequent coexistence of FCHL and Hyperabeta?

A

Three gene clusters have been associated with FCHL, one of which is involved in apoB/LDL metabolism.

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16
Q

Pt’s with FCHL or Hyperabeta have a high risk of developing what?

A

high risk of developing CARDIOVASCULAR DISEASE.

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17
Q

How is FCHL defined?

A

It’s defined as a family that manifests a VARIETY of LIPID PHENOTYPES. (Some members have elevated TG (type IV), some have elevated total cholesterol (type IIa), and others have both (type IIb). Also, if the same individual is tested repeatedly, he can change phenotypes.)

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18
Q

How do the number and composition of VLDL particles in patients with FCHL compare to normal individuals?

A

FCHL pt’s have INCREASED NUMBER of VLDL particles, but the VLDL has a relatively NORMAL COMPOSITION.

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19
Q

What is Hyperapobeta characterized by?

A

Increase in LDL apoB levels without an increase in LDL cholesterol (normal or low)→thus, a Cholesterol-Depleted ApoB-100 LDL Particle

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20
Q

How does the Cholesterol-Depleted ApoB-100 LDL Particle of Hyperabeta compare to normal LDL?

A

It is heavier (more dense) and smaller than normal LDL but can have an increased TG content.

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21
Q

Why is easier to diagnose Hyperapobeta than FCHL?

A

It can be done with a single blood test, while FCHL requires family studies for an accurate diagnosis (you have to assess the family members).

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22
Q

What is the key metabolic characteristic of both FCHL and Hyperapobeta?

A

An increase in apoB synthesis (and, thus, VLDL particles) by the liver with essentially normal lipid composition of the VLDL.

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23
Q

VLDL appears to be normally metabolized to LDL through IDL in FCHL, resulting in what?

A

Greater numbers of LDL particles being made. Three LDL conditions could result from this situation (next three note cards)

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24
Q

Given the increase in LDL particles in FCHL, what LDL condition would result if:
a) the pt has a DEFECT IN LDL CLEARANCE in addition to the excess VLDL production?

A

1a) Then there would be an accumulation of normal appearing LDL (normal cholesterol:apoB ratio), so the patient would have a Type II phenotype (high cholesterol).

(if catabolism of VLDL to IDL was reduced→abnormal accum of VLDL-TG in plasma→Type IIb phenotype: high TG and cholesterol)

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25
Q

Given the increase in LDL particles in FCHL, what LDL condition would result if:
b) there were a REDUCTION IN THE ACCUMULATION OF CHOLESTEROL into the particle as VLDL is metabolized to IDL and then LDL?

A

Then there would be an excess of LDL apoB without an increase in LDL cholesterol →HYBERAPOBETALIPOPROTEINEMIA

26
Q

Given the increase in LDL particles in FCHL, what LDL condition would result if:
c) there was an INCREASE IN LDL CLEARANCE that matches or exceeds LDL production?

A

Then there would be normal or low concentrations of LDL apoB and cholesterol.

27
Q

If there is a need to transport more lipids, what is the usual solution? Why?

A

Normally, apoB synthesis is RELATIVELY CONSTANT. Therefore, if there is a need to transport more lipid, the USUAL SOLUTION IS TO FORM LARGER PARTICLES.

(for example, in the gut, B-48 is secreted at a constant rate, but when fat is ingested, much larger CM particles are secreted than during fasting)

28
Q

What is a genetic disorder that is characterized by TG over-production?

A

Familial Hypertriglyceridemia (FHT)

29
Q

What are the characteristics of FHT?

A

a) VLDL apoB production by the liver and plasma concentration are normal (or only slightly increased),
b) LIVER TG PRODUCTION, TG PLASMA CONCENTRATION, AND TG/ApoB RATIO IN VLDL ARE HIGH. (VLDLs are very large)
Type IV phenotype (high TG only)

30
Q

Are FHT pt’s susceptible to CV disease?

A

Their susceptibility to CV disease is variable. IF A PATIENT COMES FROM A FAMILY WITH A HIGH INCIDENCE OF CVD, HE/SHE APPEARS TO BE PRONE TO DEVELOP CVD. However, if they come from family with little CVD, they are at no increased risk for CVD.

31
Q

Why will the HDL-C plasma concentration not differentiate FHT pt’s who will develop CVD from those who will not?

A

B/c it is low in both groups

32
Q

FHT pt’s with CAD are more likely to develop what?

A

Insulin Resistance

33
Q

In general, what are secondary/environmental causes of execess VLDL-TG?

A

anything that INCREASES THE AMOUNT OF FATTY ACIDS OR TG’s BEING DELIVERED TO THE LIVER will increase the synthesis and secretion of VLDL.

34
Q

What are specific examples of secondary/environmental causes of excess VLDL-TG (aka things that increase FA/TG delivery to liver)? (4)

A
  1. Dietary fat
  2. Increased visceral adipocytes
  3. High glucose
  4. Fructose and Alcohol
35
Q

How does dietary fat cause excess VLDL-TG production?

A

Dietary fat is delivered to liver via CM remnants and stimulates VLDL-TG secretion.

36
Q

How do visceral adipocytes cause excess VLDL-TG production?

A

Visceral adipocytes release large amounts of free fatty acids (FFAs) that are taken up by the liver and secreted as VLDL-TG.

37
Q

An increased number of visceral fat cells is usually in what conditions? (3)

A
  1. Hyperandrogenism in women
  2. Hypoandrogenism in men
  3. Hypercortisolism
    (insulin resistant states)
38
Q

Under what conditions does glucose cause excess VLDL-TG production? In what type of patients?

A

Glucose can be a substrate for TG synthesis in the liver, but at normal plasma glc levels (70-110), very little glc is taken up by the liver. At high glc [ ]’s (>150mg/dl) in Type 2 DM or inadequately treated Type 1 DM, more glc is transported into the liver→increased AcCoA synthesiss→increased de novo FA synthesis and VLDL-TG secretion.

39
Q

Why is TG synthesis very low in diabetic ketoacidosis?

A

some insulin is required for TG synthesis (there is plenty of insulin in T2DM and inadequately treated T1DM)

40
Q

How can you reduce the VLDL-TG and apoB production and plasma levels in these diabetics patients?

A

REDUCE THE BLOOD GLUCOSE

by diet, exercise, sulfonylurea, metformin, pioglitazone, or insulin therapy

41
Q

Why do diets high in FRUCTOSE/SUCROSE AND ALCOHOL increase VLDL-TG production?

A

Fructose and alcohol are good substrates for TG synthesis and are rapidly taken up by liver at all concentrations.

42
Q

What is a common cause of excess VLDL cholesterol?

A

The ingestion of certain SATURATED FATTY ACIDS

43
Q

How does ingestion of certain saturated fatty acids cause hypercholesterolemia? (2)

A

1) they stimulate cholesterol synthesis in the liver (increased VLDL cholesterol)
2) they also downregulate LDL receptors, thus inhibiting LDL clearance and increasing LDL-C in the plasma
Thus increased cholesterol synthesis and decreased cholesterol clearance→hypercholesterolemia

44
Q

A viscerally obese diabetic with poor blood glc control who eats a high saturated fat, high sucrose diet is very likely to have excess VLDL production. However, THIS DOES NOT GUARANTEE she will have high plasma TG or cholesterol levels. Why?

A

This person may have inherited a super catabolic mechanism to clear this excess VLDL.

45
Q

It is very likely that people with excessive VLDL production are at an increased risk of developing what?

A

CV disease (CVD)

46
Q

Once CMs and VLDL are released into the circulation, the TG in their core is removed by what enzyme?

A

Lipoprotein Lipase (LPL)

47
Q

In what cells is LPL synthesized?

A

adipose cells, muscle cells, macrophages

48
Q

What does LPL specifically do?

A

LPL specifically hydrolyses TG’s in CM and VLDL to free fatty acids (FFAs) and monoglycerides (MGs).

49
Q

What two smaller apolipoproteins modulate LPL?

A
  1. ApoC-II is REQUIRED for normal activity of LPL.

2. ApoC-III INHIBITS LPL activity.

50
Q

What do homozygous deficiencies of either LPL or apoC-II lead to?

A

Severe Hypertriglyceridemia in INFANTS→Type I Hyperlipidemia (>1000mg/dl)

(b/c they can’t clear TG from the circulation)

51
Q

What condition is associated with very low LPL activity and high TG concentration (can be >10,000 mg/dl)? Why?

A

DIABETIC KETOACIDOSIS (severe insulin deficiency) is associated with very low LPL activity and high TG b/c LPL biosynthesis requires some minimal amount of insulin.

52
Q

When plasma TG is >800 mg/dl, there is substantial what?

A

There is substantial accumulation of CHYLOMICRONS (CMs) in the plasma.

(since VLDL-TG production should be low in severe insulin deficiency, this massive amount of TG comes from dietary fat and is mostly present in CMs)

53
Q

Usually, pt’s with T2DM have plasma concentrations of insulin adequate to maintain normal LPL synthesis. However, in some cases they get moderate hypertriglyceridemia. Why? What type of type of hyperlipidemia is this?

A

In SOME CASES of T2DM, there appears to be a FUNCTIONAL ABNORMALITY (possible excess apoC-III) of LPL leading to slow clearance of TG. SInce T2DM pt’s have very high VLDL-TG prodcution, even a SLIGHTLY ABNORMAL CLEARANCE OF TG WILL USUALLY LEAD TO MODERATE HYPERTRIGYLCERIDEMIA→Type IV Hyperlipidemia (150 to 800 mg/dl)

54
Q

A further increase in VLDL production in T2DM (due to worsening blood glc control) combined with this subtle defect in LPL can lead to what type of hyperlipidemia?

A

It can overwhelm the LPL such that it can no longer adequately metabolize CM-TG, which can lead to SEVERE HYPERTRIGLYCERIDEMIA WITH INCREASED VLDL AND CMs→ Type V HLP (>800 mg/dl)

55
Q

What is the difference between Type I and Type V HLP?

A

Type V HLP has BOTH CMs and large VLDL (visible as a white suspension).
Type I HLP does not have large VLDL, ONLY CMs.

56
Q

How would Type I and Type V HLP plasmas look different after being left overnight in a refrigeratior?

A

Type I HLP plasma will form a CM layer (thick cream) at the top of the tube, but plasma below will be clear (no large VLDL).
Type V plasma will have the CM layer, but the plasma will look CLOUDY b/c of the large amount of large VLDL in the plasma.

57
Q

What are the relative frequencies and causes of Type I HLP and Type V HLP?

A

Type I HLP is a RARE condition, seen only when there is a GENETIC ABSENCE OF LPL or apoC-II. (infants)
Type V is MUCH MORE COMMON and is seen in patients with a combination of VLDL OVER-PRODUCTION and PARTIAL LPL ABNORMALITY. (manifests in adulthood)

58
Q

In addition to Type I and Type V HLP’s, what is the third etiology of reduced TG clearance?

A

an increase in apoC-III (an inhibitor of LPL)

59
Q

In what type of pt’s are hepatic apoC-III synthesis and plasma levels elevated?

A

Hepatic apoC-III synthesis is increased and its plasma levels are elevated in pt’s with INSULIN RESISTANCE→Type 2 DM and Chronic Renal Insufficiency.

60
Q

Plasma TG levels appear to correlate better with apoC-II or apoC-III?

A

ApoC-III

(pt’s w/ insulin resistance also have elevated apoC-II, but apoC-III appears to be a stronger inhibitor than C-II is a stimulator.)

CV Module (5 decks)

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