Lipids and Lipoproteins

Question 1

what are the features of Isoprenoids

Answer 1

-three acetyl CoA (a 2 compound acetyl CoA) to generate a IPP (isopentenyl pyrophosphate) a 5 C compound

IPP which serves as a building block for synthesis of all isoprenoids

these include steroids, lipid soluble vitamins, ubiquinone, and prenyl groups to anchor proteins to Plasma membranes

Question 2

what are the sources of Acetyl CoA

Answer 2

generated in Mitochondria via

• pyruvate
• fatty acids
• Amino acids

then transported to cytoplasm via the citrate shuttle

Question 3

what is the back bone of steroids

Answer 3

six units of IPP to make a tetracyclic sterane ring

serves as back bone of steroids

Question 4

what is the structure of cholesterole

Answer 4

Allicyclic compound made of 4 fused rings

has 27 carbons

and one hydroxyl group at C 3

Question 5

characteristics of cholesterol

Answer 5

found in Plasma membranes and things like bile acids and bile salts, vitamin D, steroid hormones (progesterone, aldosterone, cortisol, testosterone, estradiol)

cells cant degrade steroid nucleus of cholesterol

must be used biochemically or excreted by liver, Excess cholesterol can lead to athersclerosis

Question 6

how much cholesterol is produced

Answer 6

0.75 - 1 gram made in the liver but also in small intestine, adrenal cortex, ovaries, testes, and skin’

biosynthesis inversely proportional to dietary intake

Question 7

what does cholesterol need to be made

Answer 7

18 acetyl CoA 18 ATP 16 NADPH and will finish with 27 carbons

Question 8

Phase 1 of making cholesterol

Answer 8

Acetyl CoA

Acetoacetyl CoA

HMG CoA
-enzyme used to make this is HMG CoA synthetase

Mevalonate
-enzyme used to make this HMG CoA reductase (rate limiting step)

then to IPP

Question 9

Phase II of making cholesterol

Answer 9

IPP to make Squalene

lanosterol

cholesterol

Question 10

what inhibits HMG CoA reductase and some side effects

Answer 10

Statins used to lower amount of cholesterol
-lovastatin, simvastatin, pravastatin, atorvastatin

can lower up to 60 percent of cholesterol

very strong competitive inhibitor

• Ki is 5-45 nM compared to natural 4 uM
• binds in cytosol of the catalytic domain

also has a hypocholesterolemic action by increasing SREBP maturation to increase transcription of LDL receptor and help clear cholesterol in blood via LDL mediated endocytosis

Myotoxic side effects: duue to inhibit production of IPP which is important in the production of ubiquinone (CoQ) impairing mitochondrial function and then degeneration of myocytes
-can supplement this though

Question 11

what is the fate of cholesterol

Answer 11

cholesterol is esterfied to cholesterol esters by the enzyme Acyl CoA cholesterol acyltransferase (ACAT)

then is packaged into VLDL and released into the blood to go to various organs to be used

Question 12

what is the regulation on Cholesterol synthesis

Answer 12

regulated at rate limiting step

• Direct inhibition by free fatty acids, bile acids, and statins
• Covalent modifications: enzyme is inactive when phosphorylated and activated when dephosphorylated

in low energy, high AMP, activate AMPK will phosphorylate HMG CoA reductase

• insulin will activate HMG CoA reductase
• glucagon will deactivate HMG CoA reductase

also is controlled by transcription, translational , and post translational

Question 13

Mechanism of Transcriptional control

Answer 13

HMG CoA reductase has a sterol regatory element in its promotor region

• SREBP (binding proteins) in inactive form
• activates SCAP (SREBP clevage activating protein
• in presence of cholesterol, SREB-SCAB complex will be retained in ER due to binding of INSIG

-if low cholesterol, SREBP-SCAP complex will go to golgi and undergo proteolysis and mature to have SREBP translocate to nucleus to bind SBE to increase transcription of HMG CoA reductase

Question 14

function, and structure of Lipoproteins

Answer 14

serve as vehicles for transport of cholesterol, cholesterol esters, TAGS, and fat soluble vitamins

outer layer: monolayer of phospholipids, free cholesterol, and apolipoproteins

inner core: packed with TAGS, cholesterol, cholesterol esters

• lipoprotiens help transfer and deliver TAG
• lipoproteins help with Cholesterol homeostasis
• apolipoproteins Targeting signals/ligands
• apolipoproteins activate various enzymes

Question 15

what are the 5 different lipoproteins

Answer 15

Chylomicrons
Very low density lipoproteins (VLDL)
Intermediate density lipoproteins (IDL)
LOw density lipoproteins (LDL) (bad cholesterol)
High density lipoproteins (HDL (good cholesterol)

this is also same goes for size in that order

Question 16

what 5 lipoproteins contains the most percentage TAGS?
cholesterol?
Proteins?

Answer 16

Chylomicrons have most TAGs but least protein

LDL: highest percentage of cholesterol relatve to size

HLDL: least TAGS but highest protein make up

Question 17

structures found on a chylomicron and its properties

Answer 17

ApoB-48 : facilitates transport
ApoC-II : activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver

Exogenous and formed from dietary fats

• largest
• least dense
• High TAG

Question 18

structures found on VLDL and properties

Answer 18

ApoB-100: uptake into cells
ApoC II: activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver

• made in liver
• packaged with TAGs and cholesterol

Question 19

structures found on IDL

Answer 19

ApoB-100: uptake into cells

ApoE: facillitates uptake into liver

Question 20

Structures found on LDL and properties

Answer 20

ApoB-100: uptake into cells

bad cholesterol

no TAGs

lots of cholesterol

Question 21

structures found on HDL and properties

Answer 21

ApoA-1: activates enzyme that esterfies cholesterol
ApoC-II: activates capillary lipoprotein lipase
ApoE: promotes uptake into hepatocytes

good cholesterol

• smallest
• most dense
• high protein and phospholipid content

Question 22

Chylomicron processing

Answer 22

1) nascent chylomicrons are assembled with dietary lipids in the small intestine and transported through the lymp back to the blood stream
2) additional apoproteins are added to create a mature chylomicron (apoC-II and ApoE are supplied by HDL)
3) Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids then ApoC-II is released back to HDL
4) remnants areendocytosed by the liver via binding to ApoE to its receptor

Question 23

Type I and III proteinemia

Answer 23

these affect either the ApoC-1, ApoE or the capillary lipoprotein lipase

Question 24

VLDL, IDL and LDL processing

Answer 24

1) VLDL are assembled in the liver and released into the bloodstream
2) Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids then ApoC-II is released and now just IDL remains
3) Cholesterol in IDL is delivered back to the liver via binding ApoE to IDL receptors in liver cells

half of IDL lose more TAG via action of the hepatic lipoprotein lipase and then will lose ApoE to become LDL

4) LDL deliver their cholesterol load to the liver and peripheral tissue of ApoB-100 to LDL receptors on target cell

Question 25

how does LDL play a key role in cholesterol metabolism

Answer 25

LDL is the major carrier of cholesterol in blood LDL can carry 1500 cholesterol ester molecules shell has ApoB-100 which is recognized by receptors in target cells role of LDL is to transport cholesterol to peripheral tissues and regulate the synthesis of cholesterol

Question 26

how does the uptake of LDL occur

Answer 26

receptor mediated endocytosis ApoB-100 will bind onto an LDL receptor and then get brought into the endosome then the LDL receptor will release the LDL in the endosome due to the change in the pH one class of mutation that results in familial hypercholesterolemia generates receptors that are unable to release the LDL cargo

Question 27

HDL processing

Answer 27

1) nascent HDL is synthesized in the liver and the small instestine 2) picks up cholesterol from peripherla tissues 3) LCAT esterfies cholesterol and these will enter the HDL making it spherical 4) HDL receives ApoC-II and ApoE from chylomicrons the HDL will transfer the cholesterol to VLDL, IDL, LDL in exchange for TAGS and phospholipids via the CETP (cholesterol ester transfer protein) HDL delivers its cholesterol load to the liver

Question 28

Beneficial effects of HDL

Answer 28

High HDL correlates positively with reduced risk of CAD -because important for maturation of chylomicrons by supplying ApoC-II and ApoE plays an important role in reverse cholesterol transport by removing cholesterol from parts of tissues in the body and bringing them back to the liver -scavenges and removes LDL-cholesterol from periphery and transports it to liver where it can be recycled and processed antioxidant, anti-inflammatory, antithromotic, and nitric oxide inducing properties HDL- C levels are increased by weight loss, excersise and smoking cessation

Question 29

what protein is important for reverse cholesterol transport and can be mutated

Answer 29

Cholesterol-transport protein in endothelial cells and macrophages, APCA1 (ATP-binding cassette transporter, subfamily A1) loss of this leads to a disease called Tangier disease -HDL deficiency and accumulation of cholesterol in macrophages and premature athersclerosis

Question 30

Type I familial hyperchylomicronemia

Answer 30

Deficiency in apoC-II or defective lipoprotein lipase increase in Chylomicrons increase in Triacylglycerol

Question 31

Type IIa and IIb familial hypercholesterolemia

Answer 31

LDL receptor is completely IIa or partially IIb defective increase in cholesterol increase in triacylglycerol: normal IIa and increased in IIb increase in LDL increase in VLDL for IIb

Question 32

Tangier disease

Answer 32

hypolipoproteinemia defect in transporter that supports cholesterol pickup by nascent HDLs decrease in HDL

Question 33

Type I hyperlipoproteinemia

Answer 33

Hyperchylomicronemia inabillity to hydrolyze TAGs in chylomicrons and VLDL cause: deficiency in capillary lipoprotein lipase or ApoC-II, an essential part of LPL complex and necessary for enzyme activity Primary is an LPL deficiency manifiests in infancy ApoC-II deficiency post adolescence Plasma TAG levels are greater than 1000 mg/dL creamy appearance of blood clinical symptoms: abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas treatment = low fat diet

Question 34

Type II Hyperlipoproteinemia

Answer 34

familial hypercholesterolemia causes: defect in LDL receptor resulting in uptake of LDL via receptor mediated endocytosis increased cholesterol in blood high LDL undergoes oxidation, oxLDL leads to an inflammatory response leading to cardiovascular disease such as athersclerosis impaired abillity to reckognize ApoB-100 on LDL normal cholesterol = 130-200 heterozygous = 300-500 homozygous = >800 untreated lead to death of CAD physical symptoms: Xanthomas, corneal , deposits in eyes, and angina pectoris Heterozygous respond to diet, statins, and bile binding resins Homoygous: LDL apheresis and liver transplant

Question 35

Plasma Cholesterol and Athersclerosis

Answer 35

LDL-C levels correlate positively with Cardiovascular disease LDL-C accumulates nder the endothelial cells lining blood vessels -there the LDL will modify to become oxidized LDL -this oxLDL accumulates in the vessel wall and lead to endothelial injury leading to even more influx of LDL into arterial wall this increased vascular permeabillity and leukocyte adhesion - oxLDL initiates an inflammatory response - macrophages up take the ox LDL but become engorged forming foam cells Foam cells become trapped in the walls to form plaques -death of foam cells, platelet adhesion, and recruitment of smooth muscle cells leads to further development of arterial plaque that eventually leads to athersclerosis narrowing of arteries by the plaques lead to heart attacks