MCP Flashcards
What is Sitosterolemia?
Autosomal recessive disease caused by the mutation in the ABCG5/8 genes that encode the ABC transporters for sterolin-1 and 2. Diminshed plant sterols (made with cholesterol) are pumped back into the intestine and excreted from the liver. Causes an increase in phytosterols found in the blood and tissues. Tendon/Tuberous xanthomas seen, increase propensity towards coronary atherosclerosis and coronary heart disease.
How is cholesterol synthesized in the body?
Done by all cells except RBC. Done on the cytoplasmic surface of the smooth ER. Two molecules of Acetyl CoA condense via Thiolase to form Acetoacetyl CoA. A third molecule of acetyl CoA is added by HMG-CoA synthase forming HMG CoA.
This is the beginning of the synthesis.
What is the rate limiting step of cholesterol synthesis?
TEST Question.
Conversion of HMG coA to mevalonate which is done by HMG coA reductase. HMG coA reductase is inhibited by cholesterol. This reaction require 2 molecules of NADPH. CoA is released during this rxn.
Name the eight steps for converting mevalonate to cholesterol….
1) 6C Mevalonate uses 2 ATPs to be converted to 5 pyrophosphomevalonate
2) 5 pyrophosphomevalonate is decarboxylated to form IPP (5C) ATP is needed.
3) IPP is isomerized to DPP.
4) Another IPP is added to DPP to form a 10 C GPP
5) IPP is added to GPP to form 15C FPP (prenylation)
6) Two FPP and combined releasing pyrophosphate. NADPH is needed. Squalene is formed. ( 18 ATP used).
7) Squalene converted to lanosterol using NADPH
8) Lanosterol to Cholesterol by removing 3 Carbons ( 27C)
What is Smith Lemli Opitz Syndrome?
Disorder of cholesterol biosynthesis due to deficiency in 7 dehydrocholesterol 7 reductase which is the enzyme rhat converts lanosterol to cholesterol.
How is cholesterol synthesis regulated?
1) HMG CoA reductase is regulated by the transcription factor SREBP -2 which binds to cid acting sterol regulatory element ( SRE). SREBP2 when inactive is part of the ER membrane protein and is associated with SCAP ( another ER membrane protein). When cholesterol levels are low, SREBP2/SCAP complex move to the golgi where SREBP is cleaved that activates transcription factors to increase cholesterol production. When cholesterol is high, it binds to SCAP making it unable to leave the ER and be cleaved by the golgi.
2) Cholesterol also binds to the reductase itself which promotes ubiquitination and degradation of the enzyme.
3) low ATP and high AMP induces a phosphoylated enzyme which makes it inactive and reduce cholesterol synthesis.
4) Insulin and Thyroxine upregulate the expression of HMG CoA reductase. Glucagon and the glucocoticoids down regulate expression.
What are Statin Drugs?
Structual analogs of HMG coA reductase and is used to lower plasma levels of cholesterol.
What are the two most common bile acids
Cholic Acid ( 3OH/ Triol) Chenodeoxycholic acid (2 OH/Diol)
How is bile Acid synthesized?
OH groups are added to cholesterol and NaDPH is used. It is done by cholesterol 7-aplha-hydroxylase ( addition of hyroxyl group at Carbon 7) which is inhibited by bile acids ( cholic or Chenodeoycholic).
Bile before it leaves the liver is conjugated to either serine or taurine. Forming glycocholic or taurochendoycholic. Forming BILE SALTS.
How is secondary bile salts formed?
Bacteria in the intestinal lumen remove the hyroxyl group from the 7 C.
How are Bile Salts recirculated?
Bile Salts are reabsorbed in the ileum and NA/Bile salt transporter. Binds to albumin to transport it in the blood. Heptocytes take up the bile salts. Called Enterohepatic Circulation.
What is Cholelithiasis?
GallStones caused by an increase in cholesterol or a decrease in bile salts making the liquid insoluble and forming stones.
Movement of cholesterol into the bile must be accompanied by bile salt and phospholipid secretion. Disruption of this dual secretion process causes insolubility
What are the types of Lipoproteins?
Chylomicrons: Highest Lipid, Lowest Protein, Low density ( largest)
VLDL
IDL
LDL
HDL- High Density due to High Protein and Low Lipid Ratio. Smallest Size
Lipid deposition leads to plaque formation and causes narrowing of blood vessels ( atherosclerosis).
They have an inner hydrophobic core of TG and cholesterol. It is surrounded by amphipathic phospholipids, unesterified cholesterol and apolipoproteins.
What do apolipoproteins do?
Provide recognition sites for cell surface receptors
Activators for enzyme involved in lipoprotein metabolism.
Apo A 1- Most abundant in HDL. Involved in Reverse Cholesterol Transport and synthesized in the liver/intestine. antiatherogenic
Apo A-2: Synthesized in liver. Present with A 1 on HDL. Activated LPL and inhibits LCAT (HDL synthesis?). Proatherogenic.
B 100: Produced in liver and assembles VLDL. Higher ApoB 100 are associated with CVD.
ApoB 48: produced in intestine. Involved in CM metabolism.
C 1,2,3: Important for TG metabolism. Interfere with the recognition of apoE by LP receptors. C2 activates LPL and C3 inhibits LPL.
ApoE: Associated with all LP except LDL. Responsible for the clearance of intestinal derived LPs after a meal and for clearance of VDL and IDL before it goes to LDL. Three isoforms (E2,3,4).
- E3:most common
- E2: Binds poorly to receptors. risk factor for dysbetalipoproteinemia ( Type 3 hyperlipedmia : Elevated CM and VLDL).
- E4: Alzeimers disease
How are chylomicrons formed?
Small intestine secrete nascent TAG rich chylomicrons which has ApoB 48 on it ( entire gene encodes for ApoB 100). This transfer of apoB is done by microsomal TG transfer protein (MTP).
In the blood it receives ApoE ( recognized by hepatic receptors) and ApoC2 from HDL particles.
Extracellular ezyme LPL is attached by heparin sulfate to the capillary walls in most tissues. LPL is activated by ApoC2 it hydrolyzes TAG yielding fatty acids/gylcerol. Fatty acids are stored and the glycerol is used in the liver for lipid synthesis/gluconeogenesis.
Particle then decreases in size and increases in density. ApoC return to HDL creating a chylomicron remnant.
Chylomicron remnant taken up by the liver via the ApoE binding.
What is LPL?
Antiparallel homodimer. N terminus contains the lypolytic site and the C terminus brings to the lipoprotein particle that gives substrate specificity. APo C binds, the N terminal supplies the lipid to the C terminal so that TAG can be degraded.
LPL increases in the adipose tissue in the fed state ( elevated insulin) and the muscle LPL is decreases.
LPL or ApoC 2 (type 1 hyperlipoproteinemia or familial LPL deficiency) accumulate chylomicron TAG in the plasma and are at high risk for pancreatitis.
VLDL Metabolism?
VLDLs are produced in the liver and secreted into the blood by the liver with apoB 100 s a nascent particle. They obtain ApoC and E from HDL particles. TAGS are exchanged for cholesterol esters by cholesterol exchange protein with HDL.
TAG is degraded in the capillaries by LPL via ApoC activation. VLDL then becomes LDL in th blood with IDL remnants. ApoC and E are returned to the HDL.
LDL particle binds to specific receptor on hepatocytes and extra hepatic tissue and are endocytosed.
What is hepatic Steatosis?
Nonalcoholic fatty liver disease and there is an imbalance between TAG synthesis and secretion of VLDL.
What is Cholesterol Ester Transfer Protein?
CETP catalyzes the exchange of TAG from VLDL to HLD in exchange for CE from HDL to VLDL. The greater the TG concentration, the greater the rate of exchange. High TG containing LP in blood correlates with greater cholesterol return to liver via VLDL and IDL.
What is ACAT?
If cholesterol is not needed immediately it can be esterified by Acyl CoA: cholesterol acyl transferase (ACAT). Resulting in a cholesterol ester than can be stored in the cell. ACAT in increased by the presence or oversupply of intracellular cholesterol.
LDL uptake and degradation steps
KNOW FOR TEST!
LDL have much less TAG than VLDL and more cholesterol and cholesterol esters. LDL provides cholesterol to the pheripheal tissues and return it to the liver.
1) LDL receptors are clathrin coated pits which recognize ApoB 100 and E.
2) Clathrin vesicles fuse with endosome due to low Ph.
3) Ph in endosome drops based on ATP proton pump uncoupling the LDL with receptor. Separate into distinct areas of what is called Compartment for Uncoupling Receptor and Ligand ( CURL).
4) Lysosomal hydrolases once fused with lysosome degrade the LDL releasing amino acids, fatty acids, cholesterol and phospholipids.
An oversupply of Cholesterol with inhibit HMG co reductase which synthesises cholesterol. This can also diminish Liver LDL receptors.
What is Famililal Hypercholerolemia/ Type 2 hyperlipedemia?
Deficincy in the LDL receptors causes elevated LDL plasma cholesterol. Autosomal dominant hypercholesterolemia can be caused by increased activity of a protease that degrades LDL receptors ( done by PCSK9). Or defects in ApoB 100.
What are the domains of the LDL receptor?
The protein has 6 regions:
1) LDL binding domain
2) EGF like domain : CURL compartment interaction and pH dependent for a conformational change.
3) N linked oligo
4) O linked oligo ( 3 and 4 make it more accessible for LDL particles).
5) Transmembrane domain
6) Intracellular domain: clathrin binding sites
Most Genetic Defects are found in domain 1 and 2.
HDL metabolism
Formed in the blood by addition of lipids to Apo1. HDL serves as a circulating supplier of Apo C2 and E.
Nascent HDL are dicoid in shape and contain APoA,C and E. They take up cholesterol from pheripheral tissues via ABCA1 and return it to the liver as Cholesterol esters via SRB1. It is esterified by lecithin cholesterol acyl transferase ( LCAT). LCAT is activated by apoA1. CE are transfered to VLDL via cETP. VLDL transfer to LDL and the receptors of LDL take up the CE. It then goes to the liver.
As HDL consume CE it moves from cholesterol poor HDL3 to CE rich HDL2. The conversion is done by hepatic lipase.
This is reverse cholesterol transport.
What is Tangier disease?
Deficiency in ABACA1 which leads to an absence of HDL particles because of degradation of lipid free apo A-1
How does Oxidized Lipoproteins lead to Plaque formation?
Oxidized LDL cause endothelial injury and monocytes become activated macrophages called SR-A (scavenger receptor class A)which consume excess lipoproteins becoming foam cells. Foam cells accumulate releasing Growth factors and cytokines that stimulate SMC to take up lipids becoming foam cells. Foam cells become plaque.
How do Plaques influence CVD?
Once the plaques ruptures, the plaque is healed via a thrombus. If the thrombus grows to completely occlude the blood vessel. Acute MI can occur.
5 Major Receptors in Lipid Metabolism
1) LDLR : recognizes ApoB 100 and ApoE . Regulates entry of cholesterol into the cell and LDLs. Deficiency causes Familial Hyperchoesterolemia.
2) LDLR- related protein: Recognizes ApoE only. Mediates the uptake of chylomicron remnants and VLDL. MEtabolizes ApoE lipoproteins but not LDL.
3) PCSK9: Protein that modulates the LDLR. Upregulation casues degratation of the LDLR and elevation of LDL. Down regulation is associated with decrease in LDL and low risk of CAD.
4) Scavenger Class A: Recognizes oxidized LDL: Mediates the uptakes of these into macrophages. High cholesterol does not suppress scavenger receptors, causing foam cells and early atheroclososis.
5) Scavenger Receptor B: Includes CD36 and SR-B1. Recognizes HDL. It accepts cholesterol from HDL by the liver and steroid producing cells.
General Characteristics of Steroid hormones?
Cholesterol is the precursor to hormones.
Glucocorticoids: Adrenal (cortisol)
Mineralcorticoids: aldosterone
Sex Hormones: androgens
They are bound to proteins when they travel in the blood and bind inside the cell on nucleus receptors.
How are steroid hormones synthesized?
Shortening of the hydrocarbon chain of cholesterol and hydroxylating the steroid nucleus. Rate limiting step is conversion of cholesterol to 21 C pregnenolone. done by desmolase/CYP11A/P450scc. The reaction requires NADPH and O2. It is in the inner mitochondria membrane. Cholesterol transfer to IMM is done by STAR (steriodogenic acute regulatory proetin).
What is Congenital Adrenal Hyperplasia (CAH)
KNOW THIS!
1) Defect in 3 Beta Hydroxysteroid dehydrogenase. Converts pregnenolone to progesterone. No glucocoritcoids, mineralcorticoids, androgens. Salt excretion in urine. Female like genetalia.
2) Defect in 17 alpha hydroxylase deficiency stops progesterone into 17 aplha hydroprogesterone. No sex hormones or cortisol producded. Increase production of mineralcorticoids, Na and fluid retention and hypertension. Female like gentalia.
3) 21 alpha hydroxylase deficiency: stops 17 hydroprogesterone into 21 deoxycortisol/deoxycorticosterone. Most common CAH. Mineral/glucocoticosteroids virtually absent. Overproduction of androgens. .
4) 11 B hydroxylase deficiency: Stops Aldosterone and Cortisol secretion. Increase production in deoxycorticosterone ( 11 B hydroxylase converts 11 DeoC to Corticosterone). Deoxycorticosterone suppresses the renin angiotensin system, causing low renin hypertension. Overproduction of androgens
What is cortisol?
Produced in the zona fasiculata of the adrenal glands ( middle layer) and is controlled by the hypo/pituitary axis. In response to stress, CRH (corticotrophin Releasing Hormone) goes through the capillaries to the anterior pituitary producing Adrenocorticotropic hormone (ACTH). ACTH causes the adrenal cortex to synthesis glucocorticoid cortisol. Cortisol inhibits CRH and ACTH.
How does ACTH increase Cortisol production?
ACTH binds to G protein, increase cAMP, increase PKA. PKA activates lipase to convert Cholesterol Ester from LDL to Cholesterol and STAR protein that allows cholesterol into inner mitochondria membrane. It is converted to pregnenolone and then returned into the cytosol to be converted to progesterone. two ER proteins convert progesterone to 11 Deoxycortisol which is returned to inner mito membrane and CYP11B1 Beta hydroxylates leaving cortisol.
Function of Aldosterone?
Produced by the outer layer of the adrenal gland. Production stimulated by a decrease in plasma Na/K and by angiotensin 2. It increases Na and water uptake from the kidneys. Increase BP.
Ang2 produced from Ang1 by angiotension converting enzyme (ACE). ACE inhibitors used to treat renin dependent hypertension.
Sex Hormones Functions?
Androgens produced in the inner zona reticularis and middle layers of adrenal cortex. They are converted to testosterone and estrogen in peripheral tissues.
Gonadotrophin Releasing Hormone releases from the hypothalamus and stimulates LH and FSH from the anterior pituitary. They both bind to G linked protein surface receptors increasing cAMP and PKA.
LH stimulates testes to produce testosterone and ovaries to produce estrogen and progesterone.
FSH regulates the growth of ovarian follicles and stimulates spermatogenesis within the testes
Estrogen: Enzyme is Aromatase ( convert from testosterone). Inhibitors are currently used in estrogen responsive breast cancer in post menopausal women.
How do steroid hormones act on their targets?
They are hydrophobic and diffuse through the plasma membrane and bind to nuclear receptor. It binds to the hormone responsive element on the enhancer of the gene and up regulates gene transcription.
How are steroid hormones metabolized?
converted to excretion products in the liver. Reduce unsaturated bonds and introduce hydroxyl groups. Conjugate with glucoronic aside of sulfate make it more water soluble. 20-30 %are excreted into bile and then feces. The rest through kidneys and urine. No protein carrier needed since they are water soluble.
Basics of Vitamin D?
Group of sterols that act like hormones. Active molecule is 1,25 dihydroxycholecalciferol which binds to receptor proteins in the cell similar to steroid hormones and enhances transcription. It regulates Plasma Ca and Phosphorus levels.
Sources: Exogenous in plants and animal tissues
Endogenous: 7 Dehydrocholesterol is an intermediate of cholesterol biosynthesis and can be converted to cholecalciferol in the dermis when exposed to sunlight. It then goes to the liver to be converted.
How do you convert inactive to active vitamin D?
In the liver 25 hydroxylase yields 25 hydroxycholecalciferol or Calcidol ( major form of vit D in the plasma and major storage form). In the kidneys C P450 hormones hydroxylates it to 1,25 DiOH D3 ( Calcitriol). KNOW.
How is 25 hydroxycholecalciferol 1 hydroxylase regulated?
Increased by low phosphate and low plasma calcium. Low Ca triggers PTH which upregulates hydroxylase.
Hypocalcemia can cause elevated 1,25 diOH D3 due to the over regulation of PTH.
1,25 diOH D3 inhibits activity of 25 hydroxycholecalciferol 1 hydroxylase and expression of PTH ( negative feedback).
What does Calcitriol do?
Increase Ca metabolism from bone and absoprtion from the intestine. Increase renal absorption of Calcium and decrease excretion of Ca.
In the intestine it binds to a Vitamin D receptor in the cytoplasm of the intestinal cell. Enters the nucleus and binds to a vitamin D response element which enhances expression of specific proteins. Incrases of Calbindin protein occurs which mediates transport of Ca across the enterocytes from the apical side. TRPV5 allows entry of Ca into epithelium cells.
Ca transport across the enterocyte cytoplasm appears to be rate limiting for the intestine.
diminished PTH causes what on calcitriol?
Conversion of calcitriol to 24,25 DiOH D3. Calcitonin becomes elevated, inhibiting bone resportion and enhanced Ca excretion.
Vitamin D deficincy causes bone demineralization due to increase PTH. In adults it causes osteomalacia and rickets in children.
Vit D can be found in fatty fish, liver, egg yolks
normal is more than 50 nmol/L or more than 20 ng/ml
What is renal osteodystrophy?
Chronic kidney disease causes decrease vit D production and increase retention of phosphate and hypocalcemia. Increas PTH and bone dimeneralization. Treatment with Calcitriol.
Hyperparathyroidism can also cause vit D deficiency, causing low Ca and high Ph. Treat with ca and calcitriol
How can Vit D be toxic?
Loss of appetite, nausea, thirst and stupor. Enhanced Ca absorption leads to hypercalcemia leading to Ca deposits in many organs (kidneys and arteries).
it is a fat soluble vitamin so it can be stored in the body and is slowly metabolized.
