Lecture 17: HDL lipoprotein

Question 1

List the functions of HDL

Answer 1

Functions:
1) Transports excess free cholesterol back to the liver from cell membranes and from macrophages

2) Prevents fatty streak formation
3) Acts as a circulating “reservoir” of APO C and APO E (which are transferred to nascent chylomicrons and VLDL)

Question 2

Describe the synthesis, location and action of lecithin: cholesterol acyltransferase (LCAT) and the activation by apo A-1.

Answer 2

Synthesis:
- Enzyme made by the liver

Location:
-Released into the Blood

Action:

• Allows cholesteryl esters HDL to uptake them
• Gets APO A-1 to activate (recognizes HDL)
• Gains fatty acid from HDL
• Cholesteryl esters goes into HDL

Question 3

Describe the function of cholesterol ester transfer protein (CETP).

Explain how cholesterol esters from HDL can reach the liver via IDL and LDL

Answer 3

CETP:
-Protein that connects HDL and VLDL = allows HDL to takes some TAGS and VLDL takes some cholesteryl ester

How do they reach the liver?

• VDLs reach the capillaries blood and is formed into IDL’s lipoprotein lipase APO C II
• APO E allows IDL entry into liver
• If stay near living = LDL
• APO B-100 allows LDL entry into the liver

Question 4

Describe the delivery of cholesterol esters to the liver by HDL via SR-B1 (reverse cholesterol transport).

Answer 4

Goal: Take cholesterol from Plasma Membrane/macrophages –> Inside HDL –> Liver

• Macrophage takes up LDL and oxLDL and release free cholesterol into the blood using ABC-transporter and SR-B1 transporter
• HDL binds to SR-B1 and the cholesterl esters (CE) flow into the liver
• LDLs containing CE from HDL can deliver the CE via the LDL receptors

Question 5

Describe

1) Hypoalphalipoproteinemia (Tangier disease)

Answer 5

1) Hypoalphalipoproteinemia:
(Tangier Disease)

• Cause: ABCA1 defective
• Result: Less free cholesterol for LCAT –> HDL’s not filled w cholesteryl esters –> Degradation APO A1 or smaller HDLS

-Labs: High TAGs, Low HDL
Low HDL

-Symp: Oranged colored tonsils, enlarged liver/spleen, atherosclerosis

Question 6

Describe hyperlipidemia related to hypertriacylglycerolemia and hypercholesterolemia.

Answer 6

1) Hypertriacylglycerolemia:
- High cholesterol
- Hyperlipidemia Type I, IV (common) and V.
- High levels of chylomicrons (I), VLDL (IV) or both (V)

2) Hypertriacylglyercerolemia:
- High TAG
1) Hyperlipidemia Type IIa:
- High LDL (common)

3) Hyperlipidemia Type IIb:
- High LDL and High VLDL (common)

4) Hyperlipidemia Type III:
- High IDL, CM remnants and abnormal VLDL

Question 7

Estimate LDL-cholesterol and VLDL-cholesterol using the Friedewald equation

Answer 7

• Normal LDL = 100-130 mg/dL
• High LDL = >160
• Normal VLDL = 20-30 mg/dL

LDL-C= Total Cholesterol - [(HDL Cholesterol) + (TAG/5)]

VLDL= TAG/5
VLDL-C assumption: cholesterol represents about 20% of VLDL

Question 8

Describe Type I, IIa, IIb, III, IV and V hyperlipidemias

Answer 8

Type I Familial
Hyperchylomicronemia:
-milky layer in blood
Abnormality=
-High chylomicrons, creamy top layer
Deficiency =
- Lipoprotein lipase, apo CII
Risk =
-pancreatitis, Lipemia retinalis, eruptive xanthomas, hepatosplenomegaly

Type IIa Familial
Hypercholesterolemia:
Abnormality=
-High LDL
Deficiency =
-LDL receptor
Risk= Tendon xanthomas,
xanthelasmas

Type IIb Familial
Combined Hyperlipidemia:
Abnormality=
-High LDL and high VLDL
Deficiency =
-Overproduction of VLDL or
apo B-100 or also
deficient LDL-receptor
Risk=
Possibly No xanthomas?

Type III
Dysbetalipoproteinemia:
Abnormality=
-High chylomicron remnants, high IDL, abnormal Beta-VLDL
Deficiency =
-Apo E deficiency, homozygous for inefficient apo E2
Risk= 
-Palmar xanthomas and
xanthomas over elbow and knees

Type IV Familial Hyperprebetalipoproteinema:
Abnormality=
-High VLDL, (low HDL) Lipemic, turbid plasma
Deficiency=
-Lipoprotein lipase VLDL overproduction
Risk=
-Risk factor of pancreatitis

Type V Familial Mixed
Hypertriacylglycerolemia:
Abnormality=
-High chylomicrons, High VLDL Lipemic, turbid plasma
Deficiency=
-Lipoprotein lipase
APO C-II VLDL overproduction
Risk =
-Similar to Type I and Type IV

Question 9

Describe the biochemical basis for the use of statins, ezetimibe and bile acid sequestering agents in hypercholesterolemia, PCSK9-inhibitors

Describe the effect of niacin and fibrates

Answer 9

Statins:
-Inhibits hepatic cholesterol synthesis at the level of HMG-CoA reductase (Low levels free cholesterol –> LDL-R Synthesis)

Ezetimibe:
-Reduces the dietary cholesterol uptake and inhibits the cholesterol transport in the intestine

Bile Acid sequestering:
-Disrupt the enterohepatic circulation of bile
salts by reducing the re-uptake of bile acids and
bile acids are lost in feces. Hepatocytes use free
cholesterol to refill the pool which activates LDL-R
synthesis.

PCSK9-Inhibitors:
-increase hepatic LDL-R
recycling and reduce LDL-R degradation.

Niacin:
-reduces VLDL production and increases HDL cholesterol. Common side effects are flushing and nausea.

Fibrates:
-reduce VLDL production and increase lipoprotein lipase activity. Fibrates may increase HDL levels by stimulating apo A-1 synthesis in hepatocytes

Question 10

Discuss the significance of Lp(a) and LDL-B

List risk factors for coronary heart disease

Answer 10

Lp(a):

• Apo(a) linked to apo B-100 by disulfide bond
• Mat compete for binding of fibrin = may reduce the blood clot removal

LDL-B:
-Oxidized to Ox-LDL

Risk factors:
-Lipoprotein(a)

Question 11

Describe

1) Hypobetalipoproteinemia
2) Abetalipoproteinemia

Answer 11

1) Hypobetalipoproteinemia
- APO B Deficiency

2) Abetalipoproteinemia
- MTP Deficiency

Both:
-Labs: Low chylomicrons, VLDL, and LDL

• Sym:
  1) Fat malabssoroption
  2) TAG accumulation in epithelial cells of live/intestine
  2) Retinistic pigmentosa–> Progressive blindness
  3) Peripheral neuropath (Lack Vit A and E)
  4) Acanthocytosis