Lipids and Lipoproteins

Question 1

What is the building block of all isoprenoids

Answer 1

IPP

Question 2

Cholesterol is precursor for what important compounds

Answer 2

Bile acids/salts
Vitamin D
Steroid hormones

Question 3

Atherosclerosis

Answer 3

Cells are unable to degrade the steroid nucleus of cholesterol
It must be used biochemically or excreted by liver
Excess cholesterol leads to atherosclerosis

Question 4

What is rate limiting step in cholesterol synthesis

Answer 4

HMG Coa–>Mevalonate by HMG CoA reductase

Question 5

What molecules give positive feedback on HMG CoA reductase in cholesterol synthesis

Answer 5

Insulin, thyroxine

Question 6

What molecules are inhibitors of HMG CoA reductase

Answer 6

Direct: Sterols, statins, bile acids/FFA
Indirect:
-High AMP, phosphorylates HMG CoA reductase to inactivate it
-Glucagon phosphorylates HMG CoA
Translational control- Reduced by tocotrienol (member of vitamin E family) and oxylanosterol

Question 7

What molecules inhibit the final step of cholesterol synthesis

Answer 7

Azoles (i.e. miconazole)

KCN, Tamoxifen, triparanol, morpholine, AY-9944

Question 8

Statins and SREBP

Answer 8

Statins cause an increase in sterol regulatory element binding protein SREBP which leads to transcription of LDL receptor and subsequent enhanced clearance of cholesterol

Question 9

Myotoxic side effects of statins

Answer 9

Statins cause depletion of muscle levels of ubiquinone and resultant impairment of mitochondrial function. Squalestatins will inhibit enzyme that causes the drop in ubiquinone

Question 10

Fate of cholesterol for CPR purposes

Answer 10

It is esterified to cholesterol esters by Acyl CoA cholesterol acyltransferase (ACAT)
Packaged into VLDL and released into blood

Question 11

Regulation of HMGR gene transcription by SRE

Answer 11

SREBP binds SCAP (SREBP cleavage activating protein) and SREBP-SCAP complex remains inactive in the ER (by binding INSIG) while there is high cholesterol
Low sterol/cholesterol promotes release of SREBP-SCAP from ER to Golgi where it undergoes proteolysis to release mature SREBP to dimerize and go to nucleus
Binds SRE and promotes transcription of HMGR, LDLR and others

Question 12

Lipoprotein function

Answer 12

Transport TAGs to tissues, from the intestines or liver
Play role in cholesterol homeostasis, transporting it from site of synthesis, to sites of use and then liver for excretion

Question 13

Apolipoprotein function

Answer 13

Serve as cell targeting signals that bind to receptors to internalize lipoproteins
Activate various enzymes involved in lipoprotein metabolism and processing

Question 14

Lipoproteins: highest to lowest concentration of TAGs

Answer 14

Chylomicrons- most TAGs, least protein
VLDL
IDL
LDL
HDL - least TAGs, most protein

Question 15

Apolipoprotein names and functions

Answer 15

ApoB-48: facilitates transport
ApoC-11: Activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver
ApoA-1: activates enzyme that esterifies cholesterol
ApoB-100: Uptake into cells

Question 16

Chylomicron processing

Answer 16

Nascent chylomicrons are assembled with dietary lipids in small intestine and transported to blood stream
Additional apoproteins are added to create mature chylomicron (ApoC-11 and ApoE supplied by HDL)
Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and FFAs, ApoC-11 is released back to HDL
Chylomicron remnants are endocytosed by the liver via binding of ApoE to its receptor

Question 17

Mature chylomicron contains what apolipoproteins

Answer 17

ApoE
ApoC11
ApoB48

Question 18

Abetalipoproteinemia

Answer 18

Lack of ApoB48 and ApoB-100
Inability to produce chylomicrons and results in impaired uptake of fat and fat soluble vitamins from food
Lipid droplets found in small intestine

Question 19

VLDL, IDL and LDL processing

Answer 19

VLDL assembled in the liver and released into bloodstream with ApoB100, ApoC11 and ApoE
Capillary lipoproteinlipase hdyrolyzes TAGs and ApoC11 is released back to HDL, and IDL remains
Cholesterol in IDL is delivered to liver via ApoE, IDL lose more TAGs and ApoE to become LDL
LDL deliver cholesterol load to liver and peripheral tissues via binding of ApoB100 to LDL receptors on target cells

Question 20

What is the major carrier of cholesterol in the blood

Answer 20

LDL

Question 21

LDL main function

Answer 21

Transport cholesterol to peripheral tissues and regulate de novo synthesis of cholesterol at these sites

Question 22

HDL processing

Answer 22

HDL donates and receives ApoC11 and ApoE from chylomicrons
HDL transfers cholesterol esters to VLDL, IDL and LDL in exchange for TAGs and phospholipids
Exchanges are facilitated by cholesterol ester transfer protein CETP
HDL delivers its cholesterol load to the liver

Question 23

Beneficial effects of HDL

Answer 23

HDL crucial for maturation of chylomicrons
HDL retrieves cholesterol from other tissues in body to return to liver for excretion
Therefore, HDL scavenges and removes LDL-cholesterol from periphery and transports it to liver

Question 24

Macrophages and HDL cholesterol transport fail

Answer 24

When HDL transport fails, macrophages become foam cells and facilitate formation of plaques. Macrophages that collect cholesterol from LDL usually transport it to HDL

Question 25

Tangier disease

Answer 25

Under normal conditions, ApoA1 of HDL binds ABCA1 to facilitate LDL transport
Loss of ABCA1 activity results in Tangier disease, which is characterized by HDL deficiency, accumulation of cholesterol in macrophages and premature atherosclerosis

Question 26

HDL levels increased by

Answer 26

Antihypercholesteremic drugs, fibrates, estrogens, omega 3 fatty acids

Question 27

Type I hyperchylomicronemia

Answer 27

Deficiency in ApoC11 or defective lipoprotein lipase, meaning you cant hydrolyze TAGs in chylomicrons and VLDL
Increased chylomicrons and TAGs
Blood separates into cream and clear layers
Abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas
Treat with low fat diet

Question 28

Type IIa and IIb hypercholesterolemia

Answer 28

LDL receptor is completely (a) or partially (b) defective
Increased cholesterol, forms oxLDL which causes atherosclerosis
Cholesterol >800 w/homozygous mutation (die from coronary artery disease before teenage years w/o liver transplant and LDL apheresis)
Cholesterol 300-500 w/heterozygous mutation
Impaired ability to recognize ApoB100 on LDL
TAGs: Normal (IIa) increased (IIb)
Increased LDL
Increased VLDL (IIb)

Question 29

oxLDL

Answer 29

Accumulates in endothelial cells
Taken up by macrophages in unregulated manner
Macrophages/foam cells die, cause inflammatory response leading to platelet adhesion and recruitment of smooth muscle cells which causes further plaque development