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73 Cards in this Set
- Front
- Back
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Steriod nucleus
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Perhydro-cyclopentane-phenanthrene (4 ring structure)
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Sterol
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Steriod subclass with a CH3-Oh group and an aliphatic chain with more than or equal to 8 carbons on C17.
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Cholesterol Ester
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When CH3OH is esterified with a fatty acid. (hydrophilicity is reduced)
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Which cells do not synthesize CHLS?
Major sources of denovo synthesis are... |
RBC
Adrenal glands Intestine Liver Muscle Skin |
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CHLS biosynthesis...
Energy comes from... All carbons come from.... Reducing equivalents come from... |
ATP
Acetyl-CoA (18 used) NADPH |
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What is unique about the location of the CHLS synthesis?
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Steps upto Squalene synthesis occur in cytosol. (Note: HMG-COA Reductase is bound to ER memebrane so this step (mevalonate synthesis) happens on the cytosolic surface of ER.
All the steps starting with Squalene synthesis occur within the membrane. (Mixed function oxidases are located in the microsomal membrane). |
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Lanosterol produces ____ in plants.
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Phyntosterols
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Precursor to Vitamin D3 and D2.
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7-dehydroCHLS
Ergosterol |
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S1P cleaves....at which site?
S2P cleaves...at which site? |
S1P cleaves SCAP bound SREBP within the lumen of the golgi. (Releasing N-terminal fragment still bound in ER).
S2P cleaves the forementioned fragment. It is cleaved on the cytosolic side and nSREBP is released. |
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What is the function of SCAP?
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In CHLS depleted cells, it transports SREBP from ER to the golgi via ER transport vesicles.
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gp78 - its function?
How does its target proteins change in response to CHLS levels? |
gp78 - Ubiquinates proteins for proteolytic breakdown.
When High CHLS levels - gp78 ubiquinates HMG-COA Reductase. (so synthesis stops). When low CHLS levels - gp78 ubiquinates Insig-1 so SCAP can bind to SREBP and gene expression increases. (CHLS synthesis progresses). |
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How can HMG-COA reductase turnover be blocked in CHLS rich cells?
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Using proteosome inhibitors. (beceause in CHLS rich cells, gp78 is degrading HMGR using proteosomes)
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Explain what happens in a cell when CHLS levels are low.
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gp78 system...
gp78 binds to Insig1 and ubiquinates it for degradation. SREBP system... SCAP disassociates from Insig1. SCAP binds to SREBP and tranports it to Golgi. There, S1P cleaves SCAP-SREBP comples on the lumen side. Then S2p cleaves the fragment releasing bHLH segment called nSREBP. nSREBP binds to SRE and upregulates gene transcription. More HMGR and CHLS synthesis progresses. (to balance low CHLS levels) |
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Function of 7a-Hydroxylase.
Chracteristics of 7a-Hydroxylase. |
Function...Converts CHLS to 7a-hydroxyCHLS.
Chracteristics.. Mixed function oxidase. It is a CP450 protein. Endcoded by cyp7A1. |
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Summarize regulation of bile acid synthesis.
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Increases unconjugated bileacid binds to FXR. Which downregulates cyp7A1 gene (codes for 7a-hydroxylase) and so bile acid synthesis is inhibited.
High oxysterols bind to LXR and upregulate expression of cyp7A1. |
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RXR
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Forms heterodimer with LXR and FXR. Important for their function.
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Which cofactor is required by 7a-hydroxylase?
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Vitamin C
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All OH groups in bile acid are on which surface?
Which carbons have OH groups? |
Alpha side. (beta side is hydrophobic)
C3, C7 and C12 (in cholate) |
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Ileal disease
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Deficiency in the biosynthesis of bile acid/salts and or their uptake into the ileum.
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CE synthesis enzymes..
Active forms are found in.. |
ACAT and LCAT
ACAT - All cells, works in cells LCAT - In liver only. Works extracellularly only. Active only as surface component of HDL. |
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ACAT1 is major isoform in...
ACAT2 is found in... |
Macrophage.
Liver, intestine |
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Functional differences between ACAT and LCAT.
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ACAT works intracellularly to synthesize CE which will be incorporated into VLDL and Chylomicrons.
LCAT works extracellularly on the surface of HDLs to tranfer free CHLS from plasma membranes into the HDL particle to get it back to liver. |
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Lipoprotein responsible for reverse transport...
Lipoprotein to take CHLS from liver to tissues... |
HDL
LDL |
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LCAT versus ACAT
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Lecithin cHLS Acyl transferase (tranfsers CHLS to CE in HDL. Picks up CHLS from plasma membranes of tissues and tranfsers it into HDL).
ACAT - In liver and intestine. Responsible for forming CE to be used in Chylomicrons and VLDL. |
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ApoE
ApoB100 ApoC2 ApoC1 SRB1 CETP |
ApoE - For RME
ApoB100 - For LDL Receptor binding ApoC2 - LPL activation ApoC1 - LCAT cofactor SRB1 - Transport of HDL into Liver CETP - CE transfer protein. Transforms HDL into other lipoproteins. |
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Which apo protein is required for receptor mediated endocytosis (of VLDL and chlm)
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ApoE
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Which apo protein is required for LDL receptor transport?
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ApoB100 (not apoE)
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Which liver proteins is first step in HDL synthesis?
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ApoA1
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ABCA1 versus ABCG1
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ABCA1 in liver and intestine.
ABCG1 in non-steriodogenic tissues. Both transfer CHLS from plasma membrane to HDL. (this causes more LDL receptros and serum LDL drops) |
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LCAT is activated by.... and
requires ____ to function. LCAT is synthesized in... |
ApoA1
And required ApoC1 to function. Liver |
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What is the ester group on CE synthesized by LCAT?
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The FA group that was on R2 of CE. (Mostly, w9, w6 or w3)
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Compare the substrates of LCAT versu ACAT?
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LCAT - CHLS + PC
ACAT - CHSL + FA-acyl CoA |
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Which apoproteins are found on...
Nascent VLDL Mature VLDL HDL Chylomicron LDL |
Nascent VLDL - apoB100, apoE, apoC1
Mature VLDL - apoB100, apoE, apoC2 (all Cs) HDL - apoA1, apoC1, apoE, CETP, (all A and Cs) Chylomicron - apoB48, apoE, apoC2, apoA1, apoA2 LDL - apoB100, apoE |
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Which tissue has the highest levels of apoE and apoB100 LDL-Receptors?
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Liver
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What is pre-HDL (what is in it?)
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Unesterifies CHLS rich intermediate. Precursor to HDL. LCAT will transfer this CHLS to CE and mature HDL is synthesized.
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Are HDLs taken up by Liver via SRB1?
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No - SRB1 only takes in CE from the HDL. HDL particles still remain.
The endocytosis probably still happens via apoE. |
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Why is reverse transport of CHLS good?
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Because we are taking CHLS out of the cells (via HDL) and trasferring it back into Liver.
Also, this causes accumulation of LDL-R on peripheral tissues so that LDL can provide for depleted CHLS in the cytoplasm. This causes drop in serum LDL (especially old LDLs). This is why reverse transport is good. |
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Regarding LDL-R --- Mutations in which region result in recycling defects?
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Domain 2 - N-lined oligosaccharides, LDLR can be used only once (cant be recycled via endosome)
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Which kind of mutations will prevent LDLR from forming a coated pit?
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Domain 5 - Cytosolic c-terminal mutants. Coated pits can be formed, so no endocytosis and no LDL uptake (but LDL apoB100 can bind to LDLR)
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LDL-R mutants
Domain 01 Domain 02 Domain 1 Domain 2 Domain 4 Domain 5 |
Domain 01 - Promotor region
Domain 02 - Singal peptide Domain 1 - Ligand binding Domain 2 - N-linked oligosaccharide. Recycling defect. Domain 4 - Membrane spanning mutant. Degraded by proteosome. Domain 5 - Cytocolic peptide mutant. Unable to form coated pit. |
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Which receptor on the macrophage take up oxidized LDLs?
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Scavanger receptros SR-B2. CD-36
(macrophages can not breakdown nor export this CHLS and become foam cells) |
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Why do vitamins A, C and E help prevent CAD?
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Because these vitamins are anti-oxidant and prevent oxidation of LDL. (which form foam cells)
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Primary stimulation of foam cell formation is..
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inability to take up LDL. Increase in serum CHLS levels.
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Sterol transport protein..
for uptake of CHLS from intestinal lumen. For return of CHLS from enterocyte to lumen |
NPC1L1.
ABCG5/ABCG8 |
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How does ezetimibe work?
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It blocks NPC1L1 - the transport protein for sterol uptake from intestine.
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Sitosterolemia
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Caused by mutants in either ABCg5 or ABCG8 protein.
Increase of phytosterols inside the cells. |
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How do phytosterols help lower CHLS?
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They compete with CHLS to bind to NPC1L1 - the sterol uptake protein.
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ACTH stimulates synthesis of which steriod hormones?
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Cortisol and DHEA
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FSH, LH and TRF stimulate synthesis and release of...
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Testosterone and Estradiol
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PTH stimulates release of...
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1,25 OH2 Vit D3
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Angntnsn II/III system stimulates release of..
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Aldosterone
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How is cortisol synthesis regulated?
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Feedback inhibition. Cortisol feedback inhibits CRH. By REDUCING the TRANSCRIPTION of the genes for these proteins.
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What is the control step in steriod hormone synthesis?
Where does the cleavage happen? What is the product? |
Desomolase (SCC) step.
Cleavage at C20-22. Pregnenolone |
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Which enzyme is used to convert pregnenolone to progesterone?
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3-Beta hydroxysteriod dehydrogenase
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Which enzyme is absent in glomerulosa cells?
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17-alpha hydroxylase (so progesterone can't go to 17-hydroxyprogesterone, which synthesizes Cortisol).
Aldosterone is synthesized. |
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Which pathway does not require Progesterone as an intermediate for hormone synthesis?
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When going throgh DHEA.
CHLS --> Pregnenolone --> 17-hydroxypregnenolone --> DHEA --> Sex hormones |
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Deficiency in which enzyme results in no synthesis of any hormones?
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3-beta hydroxylase
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Deficiency in which enzyme results in no sex hormones or cortisol?
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17-alpha hydroxylase
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Deficiency in which enzyme results in decreased mineralocorticoid and glucocorticoid?
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21-alpha hydroxylase and 11-beta hydroxylase.
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Which two defects cause complete ...
Feminization? Masculinization? |
Feminization - Two early enzymes. 3-Beta dehydrogenase and 17 alpha hydroxylase (no sex steroid synthesis).
Masculinization - Over production of sex hormones. (no synthesis of other hormones) - Two later enzymes. 21-alpha hydroxylase and 11-beta hydroxylase. |
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Deficiency of which enzyme will only effect aldosterone levels?
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18B-Hydroxylase:18B-Hydroxysteriod DHD
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Deficiency of which enzyme would only allow synthesis of Aldosterone?
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17-alpha hydroxylase (this enzyme is absent in glomerulosa cells)
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During cortisol synthesis, which steps take place in the mitochondrion?
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Desmolase step and 11-beta hydroxylase step (first and the last step)
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ACTH stimulates cortisol synthesis by increasing transcription of....
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Desmolase, CE hydrolase and StAR protein.
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Which protein is responsible for transporting CHLS in mito?
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StAR (steroidogenic acute regulatory) protein
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What is Lipod Congenital Adrenal Hyperplasia (LCAH)
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Non-functional StAR.
Impaired adrenal and gonadal steroidogenesis. |
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What is the function of aromatase?
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Convert Testosterone to 17-beta estradiol.
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Which enzyme is used to convert testosterone to 17-beta estradiol?
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Aromatase
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What is dexamethasone?
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It is a potent glucocorticoid. (cortisol agonist)
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Testosterone is a prohormone for...
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5-alpha DHT, 5-beta DHT, Estrogen
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Functions of 5-alpha DHT versus 5-beta DHT.
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5-alpha DHT works on the same receptor as Testosterone (so same function) HOWEVER, 5-beta DHT works on different receptor so different function.
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Interlukins...
Chemokines.... |
Interlukines are cytokines that act on lymphocytes.
Chemokines are cytokines that cause chemotaxis. Responsible for homing of leukocytes to sites of infection. |
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What is the only known example of a ligand that uses Tyrosine Phosphatase type receptor?
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CD45
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