Lipid Metabolism Flashcards

Question

Describe the endogenous pathway of lipoprotein metabolism

Answer 1

synthesis of VLDL by the liver; metabolism of VLDL to IDL to LDL that are taken up by the liver and other tissues VLDLs are synthesized only by liver and assembled in ER. The VLDLs transport endogenous lipids (triglycerides and cholesterol esters) from liver to extrahepativ tissues. Only apoprotein on nascent VLDLs is apoB100. Others are attained from HDL in circulation.

Answer 2

Removal of cholesterol from peripheral tissues by HDL; Esterification and transfer to chylomicron remnants and IDL and transport to the liver

Answer 3

the remnants become smaller, apo C-II is returned to circulating HDLs, leaving apB48 and apo E in surface monolayer. The remnants bind to receptors on liver and are taken up by receptor mediated endocytosis. Apo E binds to remnant receptor, wheras both apo E and apoB48 are required for binding of remnants to LDL receptors

Answer 4

TRiglyceride in VLDLs is hydrolyzed, resulting in progressive shrinking to IDLs. As they become smaller, Apo C-II passed back to HDL, which leaves IDLs that have little affinity for LPL

Answer 5

taken up by liver or metabolized by hepatic lipase to LDLs 75% are internalized by liver following interaction of Apo E binding to remnat receptors and apoB-100 to LDL receptors. The more internalized, less in circulation, lower risk of atherosclerosis. About 25% of the IDLs are converted to LDLs by hepatic lipase, which hydrolyzes both triglycerides and phospholipids. This also results in the return of apo E to the circulating HDL pool

Answer 6

interaction of apoB100 with LDL receptor -> endocytosis. REceptors returned to plasma membrane and endosome fuses with lysosomes, where LDL particle is hydrolyzed. The rates of cholesterol uptake (LDL uptake) and cholesterol synthesis are coordinated by cellular concentration of unesterified cholesterol. About 75% of plasma LDL cleared by LDL receptor pathway. 25% removed by low affinity receptors known as scavenger receptors found on macrophages. Scavenger receptors have a low affinity for LDL, but a high affinity for oxidized LDL. The synthesis of scavenger receptors, unlike that of LDL receptors, is not regulated by the cellular concentration of cholesterol. As cholesterol accumulates, macrophages are converted to foam cells, which continue to form until they become part of an atherogenic plaque.

Answer 7

HDL synthesis occurs mostly in liver, though small amounts in intestinal cells. nascent HDL are disclike, with empty space inside with apo A, C and E on the surface. HDL serves as circulating respository of apoproteins. Apo C and E exchanged readily, but not A. The pathway of reverse cholesterol transport results in net transfer of cholesterol from peripheral tissue to liver, where it can be processed for excretion. Pathway is mediated by HDL, although HDL does not carry much cholesterol back to liver

Answer 8

Uptake of cholesterol by HDL Esterification of HDL Cholesterol Transfer of Cholesterol Esters from HDL to Lipoprotein Remnants Transfer of HDL cholesterol esters to tissues via scavenger receptor

Answer 9

Lipid poor HDL interacts with surface of cells, resulting in translocation of unesterified cholesterol from cell to surface of HDL. Binding HDL to surgace of cells requires A-1. The rate controlling step in reverse cholesterol transfer is transfer of cholesterol and phospholipids from cell to lipid poor HDL, mediated by an ATP-binding cassette transporter (ABCA1)

Answer 10

The cholesterol that has been picked up is converted to cholesterol ester by lecithin cholestrol acyl transferase (LCAT) an enzyme in plasma and loosely associated with HDL. Activity of LCAT is stimulated by apo A1. The cholesterol esters formed in this reaction can be transferred either to core of HDL or other lipoprotein remnants.

Answer 11

IDLs, LDLs and chylomicron remnants have empty space in core created by lipoprotein lipase catalyzed hydrolysis of triglycerides. Cholesterol esters can be transferred into this space in a reaction mediated by cholesterol ester transfer protein (CETP) or apoD. Since remnants contain apo B and apo E, they can be readily cleared by liver, following binding of LDL and remnant receptors. This is indirect pathway of reverse cholesterol transport.

Answer 12

HDL binds to scavenger receptor but is not endocytose, cholesterol esters are transferred to cell. Scavenger receptor B1 is expressed on liver, steridogenic tissues, and macrophages in atherosclerotic plaques. This is the direct pathway of the reverse cholesterol transport

Answer 13

transfer of cholesterol esters from HDL (steps 3 and 4) regenerate lipid poor HDL, which can reinitiate the cycle by taking up cholesterol and phospholipids from cells

Answer 14

1. dietary cholesterol delivered via chylomicron remnants de novo synthesis extrahepatic tissues cholesterol that is brought to liver by reverse cholesterol transport involving HSL LDL and IDL

Answer 15

repackaged and secreted in VLDLs secreted in bile as free cholesterol converted to bile acids

Answer 16

Dietary cholesterol - chylomicrons and chylomicron remnants endogenous cholesterol - exit liver in VLDLs which become LDLs, which is the major transport form to peripheral tissues. HDL picks it up from peripheral and starts the reverse cholesterol transport

Answer 17

ATP and NADPH

Answer 18

all nucleated cells | in cytosolic and smooth endoplasmic reticulum

Answer 19

to synthesize dolichol P, in glycoprotein biosynthesis, coQ, vit A, E, K

Answer 20

All cells have LDL receptors which are the principal vehicle for transport of cholesterol to peeriphery. LDL is taken up by receptor mediated endocytosis via Apo B100 The free cystolic cholesterol has three effects: repress synthesis of HMG CoA reductase repress synthesis of LDL receptors activates ACAT that forms cholesterol esters for storage

Answer 21

only significant pathway for cholesterol excretion prevents precipitation of cholesterol in bile emulsification of dietary fat facilitates absorption of fat soluble vitamins

Answer 22

Reactions catalyzed by microsomal mixed function oxygenases. These enzymes require molecular oxygen NADPH and cytochrom P450 and then introduce hydroxyl groups into ring in an alpha configuration. The configuration of the hydroyl grou at C3 of cholesterol is altered from the beta to the alpha configuration so that all of the hydroxyl groups project from same side of the ring system regulation: rate limiting step in the sythesis is hydroxylation at B-7 which is catalyzed by cholesterol 7alpha hydroxylase. This enzyme is inhibited by cholic acid

Answer 23

A three carbon gragment is cleaved off of the side chain and the terminal carbon is oxidized to carbozylic acid. This reaction also requires a mixed function oxygenase. The major bile acids in humans are cholic acid and chenodeoxylic acid

Answer 24

amphipathic nature of the molecule | low pKa of the side chain conjugated group

Answer 25

the carboxyl group on teh side chain of the bile acids can form amide bonds with either glycine or taurine to form conjugated bile acids. Before the amino acid can be added, the carboxyl group of the bile acid side chain is activated by the reaction with CoA to give high energy thioester. The energy is used to form amid bond. The conjugation improves emulsification properties because pKa of side chain ionizing group is lower than that of original carboxyl group. If the primary bile acid is cholic acid, the conjugated forms are either glycocholic acid or taurocholic acid. If primary bile acid is chenodeoxychoolic acid, the conjugated forms are either glycochenodeoxycholic acid or taurochenodeoxycholic acid

Answer 26

they are produced in intestines, by bacterial enzymes which caalze the removal of the 7hydroxy group and conjugated amino acid from the two priary bile acids to produce deoxycholic acid and lithocholic acid

Answer 27

the enterohepatic circulation - bile salts are the most significant form of cholesterol secretion. Though reabsorption of bile acids and salts is ver efficient. The liver secretes between 15 to 30 grams of bile acid a day with 0.5 g in feces. During digestion, bile acids are released into lumen of the small upper intestin and are reabsorbed by lower small intestin into the portal circulation where they are noncovalently bound to albumin. The process of secretion and reuptake is known as the enterohepatic circulation. One treatment for lowering cholesterol is to increase excretion of bilee acids and salts. This is accomplished by ingested agents that bind bile salts in the GI tract and are excreted in the feces, thus preventing reabsorption.

Answer 28

fatty acid synthesis (liver, sebaceous glands, adipose, lactating mammary glands) fatty acid storage and mobilization (adipose) fatty acid oxidation (most tissues)

Answer 29

synthesis occurs by sequential addition of 2 carbon units to carbozyl end. With the exception of the two carbons at the methyl end, all other carbons are donated by malonyl CoA

Answer 30

two molecules of NADPH are required for every 2 carbon fragment

Answer 31

it is the end product in most tissues of fatty acid synthesis, except in lactating mammary, where end product is 10. carbons rather than 16

Answer 32

on an acyl carrier protein to which the intermediates are covalently attached by a thioester bond its in the cytosol but requires participation of the mitochondria because the 2 carbon fragments are generated in the mitochondria

Answer 33

generation of substrates (acetyl coA, malonyl coa and NADPH) utilization of substrate to form palmitate modification of palmitate to give a diverse family of fatty acids

Answer 34

excess glucose and amino acids | stimulated by insulin

Answer 35

acetyl coa is formed in the mitochondrial matrix and must be translocated to the cytosol where fatty acid synthesis occurs. Since acetyl coa is impermeable to IMM, it is translocated as citrate

Answer 36

malic enzyme | pentose phosphate pathway

Answer 37

it is formed by carboxylation of acetyl coA. It is catalyzed by acetyl CoA carboxylase, a biotin requiring enzyme Purpose of carboxylation biotin requirement primary regulated step in fatty acid synthesis reaction requires ATP

Answer 38

acetyl-CoA + 7 Malonyl CoA + 14 NDPH + 14 H+ --> palmitoyl - CoA + 7 CO2 + 7 CoA + 14 NADP+

Answer 39

8 acetyl-CoA + 7 ATP + 14 NDPH + 14 H+ --> palmitoyl - CoA + 7 ADP + 7 CoA + 14 NADP+ + 7Pi

Answer 40

uptake of fatty acids is followed by conversion to fatty acid CoA. The fatty acids are transferred to C1 and C2 of glycerol 3P to give phosphatidic acid. the phosphate group is removed, resulting in diglycerids. TRansfer of another fatty acdi from fatty acyl coA to 3 OH diglyceride. TRansfer of another fatty acid from fatty acyl CoA to the 3 OH diglyceride results in triglyceride. The glycerol 3P is derived from glucose as an intermediate in glycolysis.

Answer 41

because no glycerol kinase in adipose tissue

Answer 42

Under basal conditions, ATGL exists on surface of lipid droplets with low activity and HSL is cytoplasmic. Re-esterification and sythesis of TAGs prevents net lipolysis. Activation of cAMP dependent kinase, from glycerol or epinephine, phosphorlyates HSL and perilipin, resulting in reordering of lipid droplet surface bringing coactivators of ATGL (CGI58) and HSL (Perilipin) together on surface of lipid droplet and increasing the efficiency of lipid hydrolysis to completion with glycerol and fatty acids as the final products. Under stimulated conditions there is no reesterification or synthesis of TAGs allowing net lipolysis.

Answer 43

if phosphoric acid group of a phospholipid is esterified to glycerol, this forms. Its in the mitochondrial membrane

Answer 44

esterification of another phophoric acid in phosphotidylglcerol in the three position of glycerol forms this. its found in the mitochondrial membrane

Answer 45

structural component of membranes enzyme activation second messenger signalling (IP3 and DAG produced by phospholipase C on PIP2) lung functions (surfactant = dipalmtoyl lecition aka dipalmtoyl phosphatidylcholine detergent function in intestine and gallbladder (components of bile)

Answer 46

fasting physical exertion stress

Answer 47

glucagon epinephrine and acth - physical exertion and stress glucocorticoids and growth hormone

Answer 48

all except brain and red blood cells

Answer 49

more than 99% are bound noncovalently to abumin, which has 3 high affinity sites for fatty acids and several low affinity sites. It can hold on average 0.5 to 1.5 fatty acid molecules are bound per molecule of albumin. less than 1% of the FFAs diffuse across membrane of tissues where they bind to fatty acid binding protein (FABP). equilibrium of bound and unbound FFAs to albumin are constantly readjusted

Answer 50

plasma free fatty acids turn over rapidly. Ther large reserve of albumin bound fatty acids couples with the short half-life results in a turnover of about 200 grams of fatty acids per day. The potential caloric value is about 1900kcal/day

Answer 51

function: release acetyl CoA and energy in form of electrons to be transfered to NADH and FADH2. Fatty acid oxidation occurs in the mitochondrial matrix.

Answer 52

1. binding to FABP | 2. Conversion to fatty acyl-coa

Answer 53

it is used to translocate long chain fatty acyl CoA across the inner mitochondrial membrane. The key enzymes are carnitine acyltransferase I (CAT-I) and carnitine acyltransferase II (CAT-II). Medium and short chain fatty acids can cross the IMM without the carnitine shuttle. Malonyl CoA is an intermediate in fatty acid synthesis and is an inhibitor of CATI.

Answer 54

very long chain acyl-CoA DH - C24-C14, C16 optimal medium chain acyl coA - C14 -C4 (optimal C8) short chain acyl coA - C6-C4

Answer 55

palmitoyl-coA + 7NAD+ + 7FAD +7CoA+7H2O --> 8 acetyl coA +7FADHs +7NADH +7H+

Answer 56

palmitoyl coA - 131 ATP | 129 ATP

Answer 57

the rate of fatty acid oxidation is determined by the availability of fatty acids and the rate at which they enter the mitochondria. The rate limiting step in betaoxidation is catalyzed by CATI (inhibited by malonyl-CoA so betaoxidation and fatty acid synthesis doesn't occur simultaneously). Since synthesis of malonylCoA is stimulated by insulin, insulin indirectly inhibits fatty acid oxidation by blocking the entry of fatty acids into mitochoncria. The availability of fatty acids as fuels for oxidation is regulated by activity of hormone-sensitive lipase in adipocytes.

Answer 58

odd chain fatty acids are oxidized by beta-oxidation. The last cleavage step rtep results in one acetyl coA and propionyl CoA. Propionyl CoA can be converted to succinyl CoA through the action of propionyl CoA carboxylase, an epimerase and methylmalonyl CoA mutase

Answer 59

they are oxidized by the pathway of beta-oxidation. However, two auxiliary enzymes are needed to ensure that the double bond is in the righ configuration and is between the alpha and beta carbons. most naturally occuring unsaturated fatty acids are of the cis configuration, wheas the unsaturated intermediate in beta-oxidation is of the trans configuration enoyl coA isomerase isomerizes the cis double bond in monounsaturated fatty acids to the correct configuration. 2,4 dienoyl CoA reductase is required in the oxidation of PUFAs to ensure that the double bond is between the alpha and beta carbons. Oxidation of PUFAs also requires enoyl CoA isomerase.

Answer 60

allosteric effectors and sites of action: CATI: inhibited by malonyl CoA Acetyl-CoA Carboxylase: activated by citrate: inhibited by fatty acyl CoA Hormonal Effects: Hormone Sensitive Lipase: activated by glucagon (cAMP dependent phosphorylation) makes substrate available for fatty acid oxidation Acetyl CoA Carboxylase: activated by insulin (promotes dephophorylation) In liver, activation of ACC and de novo fatty acid synthesis pathway raises the malonylCoA concentration and inhibits fatty acid oxidation, preventing a futile cycle

Answer 61

non lipogenic tissues such as muscle do not synthesize fatty acids and do not have the fatty acid synthase enzyme. However, acetyl-CoA carboxylase and malonyl-CoA decarboxylase are present. Upon initiation of exercise the AMP-activated protein kinase is rapidly activated. AMPK phosphorylates both ACC and MCD (activating it) thus lowering the concentration of malonyl-CoA, deinhibiting CAT-I and accelerating fatty acid oxidation to provide for the extra energy requirement

Answer 62

peroxisomes are important in the oxidation of very long chain fatty acids and branched chain fatty acids. The oxidation of fatty acids having chain lengths equal or greater than C26 begins in peroxisome and is completed in the mitochondria. The peroxisomal pathway is analogous to the mitochondrial pathway of beta-oxidation, but different isozymes are used and the energy yield is less. The FADH2 formed in the first step of each cycle cannot lead to ATP sythesis, because it is regenerated by O2 with the formation of hydrogen peroxide. When the fatty acids have been reduced to a chain length of C8-C10, they leave the peroxisomes and are taken up by mitochondria, where oxidation is completed

Answer 63

phytanic acid: a saturated fatty acid with methyl groups attached to carbons 3, ,7 ,11, 15 dietary source: vegetables, milk, and fat products derived from ruminants degraded by alpha-oxidation pathway: cannot undergo beta oxidation because of the beta carbon has a methyl group attached. oxidation starts by hydroxylation of the alpha carbon (catalyzed by alpha hydroxylase. The hydroxylation is followed by decarboxylation resulting in a C19 fatty acid that can be degrade by the beta-oxidation pathway

Answer 64

keton boodies are water soluble fuels that are derived from fatty acids. The two ketone bodies are acetoacetate and beta-hydroxybutyrate. They play an important role in fuel homeostasis by providing fuel for muscle and brain during period of fasting and starvation. When circulating concentrations of keton bodies reach 1 to 3 mM they begin to be taken up by eztrahepatic tissues and oxidized. Normally, the concentration of keton bdoes is less than 0.2 mM. After fasting for 3 days, the concentration will be 2 to # mM, and by 3 weeks of fasting, the concentration will be between 7 to 10 mM. Ketons play an important role in the adaption that allows protein to be conserved during starvation. Synthesis occurs in the mitochondria with the enzymes: thiolase, HMG-Coa synthase, HMG CoA lyase, Beta-hydroxybutyrate dehydrogenase

Answer 65

It occurs in extrahepatic tissues (not liver). It occurs in the mitochondria using the following enzymes: beta-hydroxybutyrate dehydrogenase, succinylCoA: acetoacetate-CoA transferase, thiolase

Answer 66

This insulin deficiency in diabetics leads to the uncontrolled release of fatty acids from adipose tissue, due to the persistent activation of hormone sensitive lipase. Most of these fatty acids are oxidized by the liverm producing more acetyl CoA than the liver needs. The overflow of acetyl-CoA is used for keton synthesis. Levels of ketone bodies as high as 10-20 mM can accumulate in the blood of Type I diabetics, resulting in a type of metabolic acidosis, which if untreated can be fatal. Some of the acetoacetate is spontaneously decarboxylated to acetone, resulting in fruit breath