MCP

Question 1

What is Sitosterolemia?

Answer 1

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.

Question 2

How is cholesterol synthesized in the body?

Answer 2

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.

Question 3

What is the rate limiting step of cholesterol synthesis?

TEST Question.

Answer 3

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.

Question 4

Name the eight steps for converting mevalonate to cholesterol….

Answer 4

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)

Question 5

What is Smith Lemli Opitz Syndrome?

Answer 5

Disorder of cholesterol biosynthesis due to deficiency in 7 dehydrocholesterol 7 reductase which is the enzyme rhat converts lanosterol to cholesterol.

Question 6

How is cholesterol synthesis regulated?

Answer 6

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.

Question 7

What are Statin Drugs?

Answer 7

Structual analogs of HMG coA reductase and is used to lower plasma levels of cholesterol.

Question 8

What are the two most common bile acids

Answer 8

Cholic Acid ( 3OH/ Triol)
Chenodeoxycholic acid (2 OH/Diol)

Question 9

How is bile Acid synthesized?

Answer 9

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.

Question 10

How is secondary bile salts formed?

Answer 10

Bacteria in the intestinal lumen remove the hyroxyl group from the 7 C.

Question 11

How are Bile Salts recirculated?

Answer 11

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.

Question 12

What is Cholelithiasis?

Answer 12

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

Question 13

What are the types of Lipoproteins?

Answer 13

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.

Question 14

What do apolipoproteins do?

Answer 14

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

Question 15

How are chylomicrons formed?

Answer 15

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.

Question 16

What is LPL?

Answer 16

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.

Question 17

VLDL Metabolism?

Answer 17

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.

Question 18

What is hepatic Steatosis?

Answer 18

Nonalcoholic fatty liver disease and there is an imbalance between TAG synthesis and secretion of VLDL.

Question 19

What is Cholesterol Ester Transfer Protein?

Answer 19

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.

Question 20

What is ACAT?

Answer 20

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.

Question 21

LDL uptake and degradation steps

KNOW FOR TEST!

Answer 21

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.

Question 22

What is Famililal Hypercholerolemia/ Type 2 hyperlipedemia?

Answer 22

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.

Question 23

What are the domains of the LDL receptor?

Answer 23

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.

Question 24

HDL metabolism

Answer 24

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.

Question 25

What is Tangier disease?

Answer 25

Deficiency in ABACA1 which leads to an absence of HDL particles because of degradation of lipid free apo A-1

Question 26

How does Oxidized Lipoproteins lead to Plaque formation?

Answer 26

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.

Question 27

How do Plaques influence CVD?

Answer 27

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.

Question 28

5 Major Receptors in Lipid Metabolism

Answer 28

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.

Question 29

General Characteristics of Steroid hormones?

Answer 29

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.

Question 30

How are steroid hormones synthesized?

Answer 30

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).

Question 31

What is Congenital Adrenal Hyperplasia (CAH) | KNOW THIS!

Answer 31

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

Question 32

What is cortisol?

Answer 32

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.

Question 33

How does ACTH increase Cortisol production?

Answer 33

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.

Question 34

Function of Aldosterone?

Answer 34

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.

Question 35

Sex Hormones Functions?

Answer 35

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.

Question 36

How do steroid hormones act on their targets?

Answer 36

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.

Question 37

How are steroid hormones metabolized?

Answer 37

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.

Question 38

Basics of Vitamin D?

Answer 38

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.

Question 39

How do you convert inactive to active vitamin D?

Answer 39

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.

Question 40

How is 25 hydroxycholecalciferol 1 hydroxylase regulated?

Answer 40

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).

Question 41

What does Calcitriol do?

Answer 41

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.

Question 42

diminished PTH causes what on calcitriol?

Answer 42

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

Question 43

What is renal osteodystrophy?

Answer 43

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

Question 44

How can Vit D be toxic?

Answer 44

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.

Question 45

How is Alcohol metabolized?

Answer 45

Ethanol is converted to acetate in the liver and generates NADH. 1) Ethanol is first oxidated to acetaldehyde done by alcohol dehydrogenase in the cytosol 2) Acetaldehyde dehydrogrnase in the mitocondria converting acetylaldehyde to acetate. 3) Acetat enters the blood and travels to muscle and other tissue where it is converted to acetyl CoA by acetyl coA synthetase.

Question 46

What can acetaldehyde do to the liver?

Answer 46

ADH in the cytosol converts ethanol to this but if it is not further metabolized by ALDH it can damage the liver and can enter the blood exerting toxic effects on other tissues. Causing flushing, nausea and vomiting and a distaste for alcoholic beverages. Using up NADH and decreasing the NAD availability for the reaction.

Question 47

What is MEOS?

Answer 47

When we have had too much to drink the microsomal alcohol oxidizing system kicks in which comprises of cytochrome P450 enzymes in the ER of the liver. Isozyme CYP2E1 converts ethanol to acethyaldehyde using NADPH and O2 as an electron receptor resultin gin NADP and ROH as products. 10-20% of alochol is oxidized through this. Products also included ROS resulting in oxidative stress and cellular damage. Chronic Ethanol Consumption can lead to CYP2E1 induction/expression which increases the clearance of ethanol from the blood but increases the amount of aldehyde before it can be cleared causing damage to the liver. Gastric ADH decreases as CYP2e1 increases.

Question 48

Name the ADH isozymes

Answer 48

ADH1: have the low Km/highest affinity for ethanol. High quantity in the liver. Major one in ethanol metabolism. ADH2. Found in liver and low GI tract ADH3: Inactive towards ethanol but active towards long chains alcohol ADH4: present in the upper GI ( high ethanol concentration in the upper GI converts ethanol to acetaldehyde by ADH4) and involved in medium chain alcohol oxidation.

Question 49

What is ALHD

Answer 49

Oxidizes acetaldehyde to acetate and generates NADH. It is catalyzed by the mitochondria isozyme ALDH2 which has a high affinity for acetaldehyde. The remainder is done by ALDH1. ALDH2*2 has an allelic variant which has a 23 fold higher Km and 35 fold lower Vmax and provides absolute protection against alcoholism. They get a horrible response. Alcoholics are treated with ALDH inhibitors. but if they keep on drinking then the acetaldehyde will damage their liver.

Question 50

What is Acetyl CoA synthethase?

Answer 50

It metabolizes acetate to Acetyl CoA. In the liver ASC 1 generates acetyl CoA for cholesterol and fatty acid synthesis. Other tissues have high ACS 2 isozyme which take up acetate. These can enter the TCA cycle and be oxidized to Co2.

Question 51

What does alcohol do to liver metabolism?

Answer 51

IT inhibits fatty acid oxidation and stimulates TAG synthesis via G3P leading to fatty liver and ketoacidosis (due to high acteyl coA and inhibited TCA cycle due to high NADH). Lactic acidosis occurs ( cannot go to gluconeogenesis because NADH shunts it to the lactate dehydrogenase cycle) causing hypoglycemia. hyperglycemia can occur if drinking with a meal because the high NADH/NAD ratio inhibits glycolysis at the Glyceraldehyde 3P dehydrogenase step. The Lactic acid also inhibits Uric acid excretion by the kidneys which increases uric acid and gout patients are advised not to drink. This is due to the increases NADH/NAD ratio. Acetyladehyde and ROS can result in alcohol induced hepatitis characterized by liver inflammation and necrotic cell death.

Question 52

How does chronic Alcohol consumption effect the body?

Answer 52

Increased acetylaldehyde and ROS: Acetaldehyde forms adducts with amino and sufhydryl groups causing a decrease in protein synthesis. adducts cause water to enter into the hepatocytes, resulting in swelling and portal hypertension. Cell damage causes release of hepatic enzyme such as alanine aminotransferase ALT and aspartate amino transferase AST. Acetaldehyde forms adducts with GSH and other antioxidants so they cannot protect against ROS which cause cell damage. ROS is increased by MEOS and also lipid peroxiation. Lipid peroxidation and oxidative damage of proteins inhibits electron transport and diminishes acthylaldehyde to acetate. Adducts with tubulin causes decreased secretion of plasma proteins and VLDL from liver. proteins accumulate in liver.

Question 53

What happens in liver cirrhosis

Answer 53

Damage is irreversible. As liver looses function the liver beomes shrunken. An inability to incorporate amino groups into urea lead to toxic levels of ammonia and increased bilirubin in blood. Increased blood bilirubin causes jaundice.

Question 54

How does vitamin deficiency occur?

Answer 54

Most vitamins are co enzymes and deficiency arise from a loss of enzyme activity. Deficiencies arise from poor nutrition, increased demand for growth,pregnancy, lactation. problems with absorption ( celiac) and interactions with medications.

Question 55

How are vitamins classified?

Answer 55

Lipid soluble: vitamins A,D,K,E Stored more effectively than water soluble and resembles lipid. Deficiencies do not arise quickly. Toxicity may be a problem. Water Soluble: B and C more hydrophilic, deficiencies can arise rapidly if vitamin is unavailable and are less likely to be toxic

Question 56

Vitamin A...

Answer 56

Most Common deficiency from poverty,premature babies. Found in egg yolks, liver, butter, whole milk, carotenoids in dark green and yellow veggies. Carotenoids are precursors to retinoid. Fctns: Visual cycle ( rhodopsin and cone opsins). Retinoic acid that acts as a hormone. antioxidant. Synthesis of certain glycoproteins and mucopolysaccharides. Deficiency: night blindness (early) and xeropthalamia ( fail to produce tears/overgrowth over cornea- advanced). Follicular hyperkeratosis(small bumps on skin), anemia, poor growth and increased risk for cancer. Toxicity: accumulates in the liver and can be toxic usually due to supplementation. Nausea, diarrhea, bone pain, scaly skin and orange cast to skin.

Question 57

Vitamin D....

Answer 57

Sources: Skin by sunlight. Saltwater fish (salmon), liver, egg yolk. ( Butter, milk fortified with D2) High levels can be toxic ( High Ca and bone loss) but are seen to be beneficial. Functions: Maintaining Bone and Ca homeostasis. Deficiency: Rickets in children( soft pliable bones), Osteomalacia in adults (loss of minerals from preexisting bone). Increased risk for breast (esp in post menopausal) and other cancers, metabolic diabetes and infection. Susceptible groups: poor, elderly, alcoholic.

Question 58

Vitamin K....

Answer 58

Fcn: Localization of enzyme required for blood clotting. Catalyzes addition of gamma carboxyglutamate to clotting enzyme. Deficiency: easy bruising, bleeding and hemorrhage. Susceptible groups: Newborn infants ( do not have vit K making bacteria in gut), patient on long term antibiotics, elderly and others with fat absorption defects.

Question 59

Vitamin E...

Answer 59

Sources: It is s et of closely related compounds called tocopherols and tocotrienols. Sources are oils ( corn, sunflower, wheat germ, margarine). Fcn: Antioxidant - scavenge free radicals. Protects membranes from damage and prevents oxidation of LDL. Located in all cell and organelle membranes. Deficiency: Cardiovascular disease and neurological symptoms. Susceptible groups: patients with severe prolonged defects in absorption (celiac).

Question 60

Vitamin C..

Answer 60

Sources: Citrus fruits, green vegetables, tomatoes. Also called Ascorbic acid Fcn: cofactor for oxidases involved in collagen formation (hydroxylation of proline to lysine). Required for synthesis of steroids in stress response (synthesis of epinephrine in adrenal gland). Aids absorption of iron and antioxidant activity. Deficiency: Mild - bruising, immunocompromise. Severe- Scurvy (decreased healing to wound, osteoporosis, pinpoint hemmorrhage and anemia,fatigue, corckscrew hair, severe peridontal disease). Usually comes from poor diet or increased need in severe stress/trauma. Susceptible: people with poor diets, smokers, long term asprin, oral contraceptices, corticosteroids treatments.

Question 61

B complex vitamins subcategories...

Answer 61

Energy releasing: B1 (thiamine), B2(riboflavin), B3 (niacin), Biotin, Pantothenic Acid ( B5), Pyridoxine(B6) Deficiency: skin ( dermatitis), Swollen red tounge, glossitis, GI-diarrhea. Peripheral neuropathy- tingling of extremities, depression Hematopoietic: Folate (B9), Cobalamin( B12) Deficiencies lead to anemia.

Question 62

B1...

Answer 62

Thiamine: Cofactor in several cellular energy metabolism. Critical in Nervous system. Easily excreted and not stored in the body. Sources: yeasts, liver, whole grains, some bean, pork and fish. Deficiency: Mild: GI symptpms, depression, fatigue. Moderate: Wernicke Korsakoff syndrome ( alcholics). Mental disturbances, unsteady gate and uncoordinated eye movements. CHF. Severe: Beriberi (polished rice diet). Can be dry which has extreme muscle weakness, poly neuropathy and heart failure or wet which is the same except for edema.

Question 63

B2...

Answer 63

Riboflavin Fcns: Precursor to FMN and FAD, Key coenzymes for redox reaction involved in energy metabolism. Source: milk, yogurt, cheese, meat, eggs, broccoli, asparagus, oranges, and whole grain foods. Deficiency: Ariboflavinosis: rash around nose, inflammation of mouth and tongue, burning and itchy eyes, light sensitivity. Susceptible groups: alcoholics.

Question 64

B3..

Answer 64

Niacin Fcns: Precursor to NAD and NADP. Coenzymes important in redox reactions. Given to patients with hypercholesterolemia or hypertriglyceridemia. Sources: meat and other high protein foods, cereal grains such as oats, wheat and rice. Deficiency: Pellagra - dermatitis, diarrhea, mental symptoms. Treated with tryptophan or niacin supplements. Rough inflamed skin worsened by exposure to sunlight. Red Neck Syndrome. Susceptible: people with corn/millet based diets.

Question 65

Biotin...B7

Answer 65

Fcn: coenzyme for several carboxylases. Deficiency: Rare since it is synthesized by bacteria but can be caused by eating lots of raw eggs ( avidin present in these eggs bind biotin very tightly).

Question 66

B5...

Answer 66

Pantothenic Acid: Fcns: Required for the synthesis of CoA. Required for TCA cycle and metabolism of all fats and proteins. Found in many foods so deficiency is rare.

Question 67

B6...

Answer 67

Pyridoxine Fcns: Precursor to pyridoxyl phosphate (PLP) enzyme cofactor. Required for glycogen breakdown and synthesis of GABA and heme. Deficiency: mild: irritability, nervousness, depression severe: peripheral neuropathy, convulsions, decreased glucose tolerance, hyperhoocysteinemia, anemia. susceptible: patients treated with certain drugs ( isoniazid-TB)

Question 68

Folate..

Answer 68

B9 : precursor of tetrahydrofolate, coenzyme involved in generating precursors for DNA and protein synthesis. Def: Neural tube defect in neonates. Macrocytic anemia. Hyperhomocysteinemia. Inhibits DNA synthesis by decreasing availability of purine and dTMP. Too much folate can mask a vitamin B12 Deficiency. Susceptible groups: pregnant women, elderly, alcoholics, patient with long term drug treatments. Genetic polymorphism.

Question 69

Cobalamin..

Answer 69

B12: coenzyme in methionine synthesis and in conversion of methymalonyl coA to succinyl CoA. Needed in folate metabolism. Stored very effectively in liver. Contains cobalt Deficiency: Pernicious anemia (megaloblastic anemia with demyelination) Seen in elderly due to lack of intrinsic factor. Susceptible: Elderly, malabsorption disease (needs intrinisic factor to release B12 from food), long term vegetarians

Question 70

What vitamin deficiencies cause Megaloblastic anemia?

Answer 70

Vitamin B12 (cobalamin) and B9 (folate) due to the deficiency in nucleotides leading to decreased DNA/RNA synthesis. Cell increase in size without dividing and large immature RBCs do not carry sufficient oxygen.

Question 71

Calcium...

Answer 71

Macrominerals : Major component of bone, used in signaling, coagulation, muscle contraction and neurotransmission. Def: mild muscle cramps, osteoporosis and severe: rickets. Susceptible: children, adults, women, eldery

Question 72

Magnesium...

Answer 72

Functions: Essential for many enzymes using MgATP as substrate. Present in high levels in the bone. Deficiency: Weakness, tremors, cardiac, arrhythmia. Susceptible: alcoholics,patients taking diuretics, severe vomiting and diarrhea.

Question 73

Phosphorus...

Answer 73

Macronutrient: Major component of bone and constituent of nucleic acids, membrane lipids. Required in all energy producing reactions. Def: Rare- rickets, muscle weakness, seizures.

Question 74

Iron...

Answer 74

Micromineral: O2/CO2 transport in hemoglobin. Oxidative phosphorylation. Cofactor in several nonheme iron proteins and cytochromes. Def: Microcytic hypochromic anemia. Decreased immunity. Sus: menstruating women, pregnant women, children Reduction of Fe3+ to Fe2+ is promoted by vitamin C in diet. Low pH in stomach removes Fe from food. Fe3+ needs ferroportin to absorp Fe3+ and convert to Fe2

Question 75

Characteristics of microcytic anemia..

Answer 75

Small pale RBC. Less hemoglobin produced and RBC undergo more cell divisions in bone marrow waiting for hemoglobin synthesis.

Question 76

Iron Toxicity...

Answer 76

Long Term: Hemochromatosis : iron overload leads to iron deposits in multiple tissues. Compromised liver, pancreatic and cardiac function. compromise mitocondial fcn leading to lactic acidosis. Acute: Overdose in kids is the most common cause of death due to toxicity in children

Question 77

Copper...

Answer 77

Micromineral: Assists iron absorption through ceruloplasmin which oxidized Fe2 to Fe3 to bind with transferrin. Cofactor in enzymes for eliminaiton of ROS (SOD), collagen synthesis and fatty acid metabolism. Def: Rare- anemia, hypercholesterolemia, bone demineralization, demylination. Sus: Menkes syndrme (mutation in Cu transporter ATP7A) or consuming excessive zinc. WIlsons disease, mutation in ATP78 results in Cu overload. Accumulates in liver.

Question 78

Zinc..

Answer 78

Micromineral: Fcn: cofactor for 300 metalloenzymes. Zn finger domains in structrual proteins. Def: Poor wound healing, dermatitis, reduced taste acuity, poor growth and impaired sexual development in children. Susceptible: alcoholics, elderly, malabsorption and kidney disease.

Question 79

Chromium...

Answer 79

Micromineral: Components of chromodulin which facilitates insulin binding to its receptor. Deficiency: Impaired glucose tolerance Sus: THose with impaired glucose tolerance, Cr3 is not a helpful treatment in diabetes.

Question 80

Iodine...

Answer 80

Micominerals: Incorporated into T3/T4 and regulates BMR. Def: Goiter ( enlarged thyroid gland). Low I causes increase thyroid stimulating hormone, results in enlarger thyroid. and hyper/hypothyroidism.

Question 81

Selenium...

Answer 81

Micromineral: Component of antioxidant enzymes (glutatione peroxidase). Component of deiodinase enzyme involved in T3 and T4 metabolism. Deficincy: Keshan disease, cardiomyopathy and cretinism.

Question 82

Most common vitamin/minerals deficiencies...

Answer 82

``` Kids: iron and Ca Teens: Ca, Mg, Vit A,C B6 Women: Fe,Ca, Mg, B6, folate Elderly: B6,12,D,Zinc, Chromium Alcoholics: Folate, B6, thiamine and susceptible to multiple deficiencies. ```

Question 83

What is the chemical structure of the five most important ROS?

Answer 83

ROS are formed from incomplete reduction of oxygen. Those containing Unpaired electrons are called free radicals (superoxide and hydroxyl radical). 1) Superoxide (O2-) : Primary ROS Free radical that has moderate reactivity. 2) Hydrogen peroxide (H202): Secondary ROS Low reactivity (not a radical). 3) Hydroxyl Radical ( OH): Secondary ROS Free Radical and has the highest reactivity (e- stealer). RNOS: NO: Generated by nitric oxide synthase. Metabolizes arginine to citrulline and forms NO. NO can react with superoxide to produce peroxynitrate (ONOO-) a very reactive oxidant. 5:O2-,H202,OH,NO,ONOO-

Question 84

how the five ROS reactions are generated?

Answer 84

Mitochondria Resp Chain produces superoxide. 1-5% of electrons leak of Oxygen prematurely to form superoxide. In complex 3, semiquinone delivers one electron to O2 to produce superoxide into inter membrane space. Complex 1 allows leakage of superoxide to the matrix of mitochondria. High membrane potential causes a slower transfer of electrons from the Qo site (complex 3) causing leakage of electrons. High NADH/NAD+ ratio causes over reduction of electron transport chain. Electron Transport chain damage. Xenobiotics increase the rate of O2- preodcuction (MPTP: induces parkinsons and found in pesticides). Electron backflow in Complex 1 due to reperfusion. Overaccumulation of succinate is rapidly oxidized by complex 2/succinate dehydrogenase and leads to backflow of electrons into complex 1.

Question 85

Ways ROS can be interconverted

Answer 85

Superoxide spontaneoulsy at low concentration dismutes to oxygen and hydrogen peroxide. H202 is converted to OH by the fenton reaction. Oh radical produced by ionizind radiations

Question 86

Role of free metal ions in generating highly reactive hyrdoxyl radicals

Answer 86

The Fenton Reaction: Electron from free metal such as Fe3+ transfers to H202. Becomes Fe2+ and OH. The presence of iron is catalytic and an over accumulation of free ion causes oxidative stress and disease.

Question 87

Major cellular damage caused by ROS...

Answer 87

OH can cause damage to macromolecules, it is the most reactive. OH generated by the Fenton Rcn produces DNA damage since nucelic acid binds Fe well. Formation of common 8-hydroxy-2-deoxyguanosine resulting from guanosine oxidation. It is use to measure the extent of DNA damage since is mispairs with a deoxyadenosine which leads to a G-T trasversion and DNA damage. Lipid peroxidation: OH is active in lipid oxidation. Polyunsaturated acyl chains (PUFA) such as arachidonic/linoleic acids are highly susceptible to peroxidation as H close to the double bonds are highly reactive and can lose e to OH.Lipid peroxidation causes membrane damage. Produces highly reactive aldehydes such as MDA and 4-HNE ( biomarkers for lipid peroxidation) Protein carbonylation: Oxidation of amino acid side chains causing protein damage by adding reactive carbonyl functional groups on proteins. Carbonyl groups are the reactive aldehydes 4HNE. Causing loss of activity and increase in protein turnover. H202 reacts with thiol proteins forming disulfide cross links with other cysteines. This cause protein aggregation.

Question 88

ROS scavenging mechanism by cellular defense mechanism and dietary antioxidant

Answer 88

Superoxide Dismutase: converts primary ROS SO to H202. Converts two superoxide into one molecule of O2 and one less H202. Sod1: contains one atom of Cu and Zn and is very abundant in the cytosol. Missense mutation cause Amyotrophic Lateral Sclerosis. Sod2: Mn as a ligand and can cross the outer but not the inner mitocondrial membrane so it degrades O2- in the matrix. Catalase/Gluthatione peroxidase/peroxiredoxin:: hydrogen peroxide is converted to water

Question 89

Role of reduced glutathione, thioredoxin, peroxiredoxin in maintaining sulfhydryl- containing proteins in a functional state...

Answer 89

Gluthatione peroxidase: GP contains Se converts H202 to water, consuming two molecules of reduced gluthatione (GSH) and producing oxidized gluthathione (GSSG) GSH is produced by gluthatione reductse which is NADPH dependent enzyme. NADPH is produced by the TCA cycle enzyme. Peroxiredoxin pathway: Perox detoxifies H202 in the mitocondria and RBC. It becomes oxidized and changes H202 to H20. Peroxi is then returned to its reduced that via thioredoxin which becomes oxidized. Thioredoxin becomes reduced again via thioredoxin reductase and that enzyme uses NADPH from the PPP of the TCA cycle. Catalse: Heme containing enzyme decomposes H202 to H20. Located in the peroxisome

Question 90

Principle of ROS mediated cellular signaling...

Answer 90

At low levels ROS fcns to promote cell proliferation and survival. Overproduction can induce oxidative damage and cell death. Redox homeostasis must be maintained. Mild oxidizing: cell differentiation. Moderate oxidizing: apoptosis and strong oxidizing: Necrosis. H202: second messenger for redox signaling. since is involved changes in the thiol/disulfide redox state of regulatory proteins. ROS is specific phagocytes undergoing a respiratory burst have an importance in innate immunity. The redox signaling also modulate transcription factors such as NF-KB which regulate expression of cytokines and chemokines that further regulate the inflammatory response. ROS are common mediators for apoptosis and cellular senescence. It prevents cancer decelopment. ROS catalyzes cardiolipin peroxidation ( in mito inner membrane) which facilitates the detachment of cytochrome c from the outer surface of the IMM and release into the cytoplasm. Antioxidants can protect healthy people from cancer but promote growth of preinitiated tumor cells.

Question 91

Connection between ROS and major human disease

Answer 91

1) Hemolytic anemia due to oxidative damage of RBC 2) ROS generation in phagocytes defect causes Chronic Granulomatous Disease 3) Oxidative damage causes reperfusion injury 4) Iron dyshomeostasis and oxidative damage in Friedreichs Ataxia.

Question 92

How is ROS generated by non mitochondria oxidases?

Answer 92

NADPH oxidases: enzymes producing superoxide in cells such as phagocytes for killing invading pathogens. Also expressed in cardiomyocytes. Xanthine oxidase/Monoamine oxidase: XO predominate in the liver and MAO are in dopamine catabolism. They both use molecular oxygen as oxidants and produce H2o2 or O2. The production of O2- and H202 contribute to oxidative stress in ischemia and reperfusion injury and the hypersensitivity of dopaminergic neurons in oxidative stress.

Question 93

Non enzymatic antioxidant defenses...

Answer 93

Antioxidants scavenge free radicals and protect proteins against sulfhydryl oxidation. 1) Coenzyme Q10 (ubiquinone): found in outer membranes and lipoproteins and ETC. Reduced form has antioxidative fcns. Scavenge RO2 radicals and inhibit lipid peroxidation. 2) Gluthathione: Free gluthathione (GSH) keeps sulfhydryls or proteins reduced and maintains biological activity. High intracellular gluthatione and high GSH:GSSG ratio is needed. If GSH:GSSH ratio is low it is an indicator of oxidative stress.

Question 94

Dietary antioxidants...

Answer 94

``` Vitamin E Vitamin C Plant Phenols Flavonoids N-Acetylcysteine, Co Q10 ```

Question 95

Molecular mechanism of obesity and metabolic syndrome...

Answer 95

Metabolic syndrome components: Visceral obesity leads to insulin resistance ( hyperglycemia and hyperinsulinemia). Causing hyperglycemia and dyslipidemia and hypertension.

Question 96

Rationale for the development of anti-obesity and anti-diabetic drugs

Answer 96

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Question 97

How is obesity defined and measured?

Answer 97

Body Mass Index. Waist circumference, waist to hip ratio, waist to height ratio and body shape index.

Question 98

Complications of obesity

Answer 98

Psychological stress, obstructive sleep apnea, joint diseases, gallbladder disease, reproductive disorders and 20% of cancer death. CVD. T2DiabetesM.

Question 99

The lipostat hypothesis...

Answer 99

Leptin signals from adipocytes which is proportional to fat accumulation in adipose tissue. Brain cells with leptin receptors sense. Hypothalamic centers influence energy intake and expenditure. An increase in leptin can cause an decrease in food intake more than energy expenditure.

Question 100

How do leptin and insulin act to control apetite and energy expenditure.

Answer 100

Ob/Ob mice behave as if starved and do not produce leptin from adipokines (obese). Injections of leptin decreased feeding and increased energy expenditure. The db mutation results in a leptin deficient receptor. it is expressed in the hypothalamus. Leptin reduces production of orecigenic effectors by the agRP neurons in the hypothalamus and by increasing the production of anorexigenic effectors by the POMC neurons in the hypothalamus.

Question 101

Implications of leptin resistance..

Answer 101

In obese people the leptin levels are extremely high suggesting insensitivity. LEptin has a limited role in body weight control in the over weighted state.

Question 102

Brown fat, membrane uncoupling and adaptive thermogenesis...

Answer 102

Adaptive thermogenesis is an evergy expedenditure: shivering is in response to cold exposure. Non-shivering: in response to cold, subject to hormonal regulation, promoted by brown fat tissue, involving well defined proteins. Regulated by brown fat tissue. BFcells are used for heat production and express high levels of uncoupling protein UCP1. BAT is formed from preursor of skeletal muscle. Beige fat cells are white adipose that has been partially converted to brown adipose with increased number of mitocondria and levels of UCP1 ( browning) UCP1 leaks protons and causes significant energectic costs. It is activated in response to cole and overfeeding. also activated by thyroid hormone receptor.

Question 103

How can drugs target metabolic syndrome?

Answer 103

Drugs either target increase energy expenditure (thyroid hormone/dinitrophenol) or reduce feeding by controlling neural circuit (phentermines - appetite supressor). Orlistats: interferes with fat absorption Locarserin promotes satiety by activating serotonin receptors in the brain. Qysmia: phentermine and topiramate (anti epileptic drug that causes weight loss). Contrave: naltrexone and bupropion which treat alcholol and drug addiction and depression respectively.

Question 104

Defining insulin resistance...

Answer 104

Failure of blood levels to decline normally in a glucose tolerance test, despite the presence of elevated levels of circulating insulin. Slow glucose disposal in the glucose tolerance test. Fast insulin level. Impaired glucose uptake into the skeletal muscle. Continued gluconeogenesis and glucose release due to less effective insulin blocking of gluconeogenic enzymes by liver increase blood glucose levels. Adipose tissues reduce glucose uptake by adipose derived substances released (adipokines) which reduces the sensitivity of muscle and liver to insulin. Lipid overaccumulation causes fat cell expansion and a state known as hypertrophy, causing reduced oxygenation and cell death. Increased macrophages at the site of injury secretes TNF alpha and proinflammatory cytokines which cause a low grade inflammation and promote insulin resistance. esp in liver. T2DM: apoptosis of islets cells.

Question 105

What is lipotoxcity?

Answer 105

The NEFA released from adipose tissue exceeds the rate of storage in obese people. Elevated circulating NEFA may promote metabolic derangements in muscle and liver. Adipose tissue secrete leptin and adiponectin which promotes B oxidation and lowered lipoylsis and reduces free fatty acids and lipotoxicity but in obesity adiponectin production is reduced - causing lipotoxicity. Increased lipid overload causing ectopic fat deposition in muscle and liver of insulin resistant individuals. FA derived diaclyglcerol (DAG) inhibits the translocation of GLUT4 to the muscle cell membrane which impairs insulin stimulated uptake of glucose into muscle cells. DAG also inhibits glycogen synthase and activates gluconeogenic enzymes in liver, increasing hepatic glucose release.

Question 106

What causes increase of DAG accumulation in muscle cells of obese individuals?

Answer 106

1) Increase caloric intake 2) defects in adipocyte metabolism 3) Gene variation in apolipoprotein C3 which reduces lipoprotein lipase. 4) mitocondrial fcn defects 5) reduced AMP activated protein kinase It may not be due to increase NEFA but a lower rate of B oxidation which is controlled by AMPK

Question 107

How does AMPK modulate insulin sensitivity?

Answer 107

AMPK is a trimeric protein kinase that is activated by AMP. In abundance AMP is phosphorylated to inactive ATP but AMP is high when starving and activates energy generating catabolic reactions. Adiponectin and leptin stimulate AMPK which stimulates FA oxidation by limiting malonyl CoA which inhibits shuffling of Fatty acyl CoA into mitocondria for oxidation. Reduced AMPK an B oxidation lead to DAG over ccumulation and insulin resistance. MEtformin phosphorylates activation of AMPK and inhibits ACC1/2 which stimulates B oxidation

Question 108

What macronutrients contribute to metabolic syndrome?

Answer 108

Fructose and alcohol because they are metabolized in the liver and their metabolism is not regulated by insulin. They do not have a mechanism for glycogen storage.

Question 109

Why does visceral fat pose a greater risk of T2DM?

Answer 109

Visceral fat has a direct venous drainage to the liver so NEFA released from visceral adipocytes may affect liver regulation. Visceral adipocytes have high expression of B3 adrenergic receptors on the cell surface which increase lipolytic response to catecholamines. Decrease response to insulin that inhibits lipolysis.They also my be more active in secreting proinflammatory molecules.

Question 110

How does exercise help with metabolic syndrome?

Answer 110

Exercise increases fat oxidation, reduces fat accumulation and stimulates AMPK activity. increasing insulin sensitivity. Exercise induces the expression of PGC1 alpha which increases muscle mitocondrial contecnt and capacity of B oxidation.

Question 111

Remodeling lipid metabolism drugs...

Answer 111

Fibrates: PPAR alpha ligands upregulate enzymes involved in B oxidation Thiazolidinediones: PPAR gamma ligands (agonists) promotes insulin action and FA uptake as well as FA storage as TG while downregulating lipolysis

Question 112

How is bile Acid synthesized?

Answer 112

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 glycine or taurine. Forming glycocholic or taurochendoycholic. Forming BILE SALTS.