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1. How many ATP are required for fatty acid activation?
2. How many FADH2 and NADH2 are produced for each cleavage in B-oxidation? How many ATP does that produce total per cleavage? How many occur?
3. How much ATP is produced per acetyl CoA? Through which reducing equivalents?
4. Total amount of ATP produced? How does this compare to glucose oxidation?
3. 12. 3 NADH, 1 FADH2, 1 GTP in TCA cycle
4. 131-2=129 for 16C. Compared to 38 ATP in glucose oxidation.
1. Why are TGs highly concentrated stores of metabolic energy? (2)
2. What is the basis for large difference in caloric yield bt fatty acids vs. proteins/carbs (9 kcal/g vs. 4 kcal/g)
3. Why are triacylglycerols stored in anhydrous form?
4. Where do most FFAs go? Where else?
5. What happens to FFAs in starvation from liver and adipose tissue?
1. Bc they are (1) anhydrous and (2) highly reduced.
2. Fatty acids are much more reduced (more bonds --> more electrons)
3. Bc they're nonpolar. Require less hydration to keep --> more efficient to carry.
4. Heart. Also go to skeletal muscle and adipose tissue and sometimes back to liver.
5. Adipose tissue increases lipolysis: TAGs --> FFAs and released into blood. Liver uptakes FFAs and re-secretes FFAs as TGs in VLDL for use in other tissues.
1. How are FFAs carried in blood?
2. How are they carried in cell?
3. What must happen before FAs can participate in any activity? Enzyme? ATP cost?
4. Describe critical steps in fatty acid oxidation (3)
1. Bound in hydrophobic pockets of albumin OR esterified in TG
2. Fatty Acid Binding Protein (FABP)
3. Must be activated by acyl CoA synthetase (adds CoA onto acyl group). 2 ATP
- 4. (1) Actiation of FA at cell membrane or outer membrane of mit via thiol-esterification of CoA
- (2) Transport through inner membrane of mit
- (3) Stepwise oxidation of fatty acid to yield acetyl CoA, NADH, and FADH2.
1. What are the relative amounts of FFA, TG, and acyl CoA in cell?
2. Why is it important that its this way?
3. What do fatty acids require to become activated? (3)
4. Can activated fatty acyl CoA pass inner met membrane? Solution?
1. TG >> FFA >> Acyl CoA, bc acyl CoA is very transitory explaining its low concentration in cell.
2. Must have low levels of hydrophobic molecules in cell, otherwise will attract inner portion of PL bilayer membrane, unfolding cell.
3. ACSL (acyl CoA synthetase), CoA, 2 ATP
4. No. CPT-1, CACT (Carnitine-acylcarnitine translocase), CPT-2
Describe how LC FAs and carnitine enter matrix (7)
What is the rate-limiting enzyme?
- 1. LCFAs enter through FATP in membrane
- 2. Acyl CoA Synthetase activates LCFA --> LCFA CoA
- 3. Carnitine enters carnitine transporter, enters outer mit membrane through CPT-1
- 4. CPT1: Acyl CoA + Carnitine --> Acylcarnitine + CoA
- 5. Acylcarnitine enters matrix via translocase.
- 6. CPTII: AcylCarnitine+ CoA --> Acyl-CoA + carnitine
- 7. Carnitine is shuttled back into inner mitochondrial for CPT1 use.
CPT-1 = rate-limiting enzyme
1. What 4 steps is B-oxidation a cycle of?
2. What are the products of B-oxidation? (4)
1. (1) Dehydration/oxidation by FAD - acyl-CoA dehydrogenase (creates double bond) (2) Hydration (gets rid of double bond) (3) Oxidation by NAD (4) Thiolysis/cleavage by CoA --> removal of acetyl CoA
2. Acyl-chain, FADH2, NADH, Acetyl CoA
What are potential problems and how are they dealt with? (2)
1. Oxidation of unsaturated fatty acids (double bonds B, gamma are not substrates for enoyl CoA hydratase)
Solution: (1) Enoyl CoA isomerase moves double bond Y,B --> a,B position OR (2) reduction by adding NADPH!!!
2. Oxidation of odd-chain fatty chains
Solution: Convert propionyl CoA --> succinyl CoA using propionyl CoA carboxylase + ATP. Succinyl CoA --> TCA.
1. When are ketones formed? (3) Why?
2. Why can't excess acetyl coA be oxidized in hepatic TCA cycle?
3. Where does ketogenesis occur?
1. Starvation, ketogenic diet, diabetes bc of excess fat catabolism --> excess acetyl CoA production
2. I DONT KNOW I SHOULD FIND OUT
1. Why do you have formation of ketone bodies in diabetes?
2. As fasting duration increases, what happens to ketone production? Why?
3. Are they water-soluble? What are they the circulating form of? What are the main ones? (2)
1. For similar reasons to starvation --> low insulin levels & high FA oxidation cause excess of acetyl CoA.
2. Increases to serve as fuel for brain/muscle (prolonged starvation --> 75% of brain's fuel needs are met by ketones). To spare glucose.
3. Yes. Acetyl CoA. B-hydroxybutyrate and acetoacetate.
Describe ketone body synthesis (3)
What can be interconverted? Using what enzyme and cofactor?
What is the major circulating ketone?
1. Condensation (thiolase): 2 acetyl CoAs --> acetoacetyl CoA (thiolester)
2. Condensation #2 (**HMG COA SYNTHASE**): Acetyl CoA + acetoacetyl CoA --> HMG COA
3. Degradation: HMG CoA Lyase: HMG CoA --> Acetoacetate + acetyl CoA
Acetyl CoA can re-enter pool of acetyl CoAs for ketone body synthesis.
B-hydroxybutryate and acetoacetate (B-hydroxybutyrate DH + NADH).
1. What enzyme is liver missing so it can't use ketones?
2. What must B-hydroxybutyrate convert to in order to be used?
3. Describe breakdown of Ketone bodies
4. Describe how high FAs end up with acetyl CoA in peripheral tissues again. (5)
5. What regulates ketone synthesis? (2)
6. Insulin's role?
1. 3-ketoacyl-CoA transferase to convert acetoacetate --> acetoacetyl CoA
3. Same as synthesis but in reverse.
4. High FA in circulation --> FAs go to liver --> ketone body synthesis (liver can't break down ) --> ketones enter circulation and are taken up by tissue with enzyme --> acetyl CoA --> TCA
5. Main driving factor: High FFAs in plasma.
Low insulin --> increases CPT-1 --> increases acetyl CoA production from B-oxidation.
6. Insulin produces Ma CoA which usually inhibist CPT-1. So insulin is low, CPT-1 is free.
1. Where does FA synthesis occur?
2. What can fatty acids go do? (6)
3. What is the starter molecule? Where does it come from? Where does it need to be imported from?
- 1. Cytosol
- 2. (1) Milk secretion (2) protein modifications (3) Complexed with FABP (4) Phospholipids (5) Regulatory pool (6) Triglycerides
3. Acetyl CoA. Pyruvate, Amino Acids, Fatty acid oxidation (not usually used for DNL). Mitochondria.
Describe mechanism of fatty acid synthesis (3)
What reducing equivalent is required?
1. Tricarboxylate transport system: AcCoA transfer --> citrate --> mitochondria --> AcCoA
2. Acetyl CoA Carboxylase + ATP (committed step): Ac CoA --> Malonyl CoA
3. Elongation (Fatty Acid Synthase --> condensing enzyme + ACP) up to 16:0
Describe transfer of Ac CoA from mitochondria --> cytosol for FA synthesis (4)
What inhibits ACC? (4) What activates it? (3)
Why is ACC master regulator of lipid metabolism?
- 1. Ac CoA --> citrate
- 2. Citrate: mit --> cytosol
- 3. ATP Citrate Lyase: Citrate --> OAA + Ac CoA
- 4. OAA --> pyruvate --> mit to make new Ac CoA.
ACC (acetyl CoA Carboxylase) is activated by citrate & insulin-dep dephosphorylation (insulin)
ACC is inhibited by LCFA & cAMP dep phosphorylation (glucagon, epinephrine)
ACC produces MaCoA which inhibits CPT-1 (B-oxidation). Skeletal and heart muscle also have CPT-1 to regulate B-oxidation (NOT FOR FA SYNTHESIS!!)
1. What special group does ACP have?
2. How does DNL start?
3. What brings in new AcCoA?
3.5 What enzyme transfers acetyl CoA to condensing region and malonyl CoA to ACP region of FASN?
4. What does condensing enzyme do?
5. After 4C is formed, describe the rest of what happens.
1. Phosphopantetheine group - essential prosthetic group of ACP (FASN) - where malonyl CoA
2. By binding MaCoA to ACP region of FASN
3. Ketoacyl-ACT synthase (condensing enzyme!!!)
3.5 MAT = malonyl/acetyl CoA acyltransferase
4. Condensing enzyme (same as above) combines malonyl CoA with acetyl CoA while releasing CO2 (also frees up ACP region for new Acetyl CoA) --> 4C molecule.
5. (1) KR uses H+ from NADPH to reduce B carbon (C=O) --> C
(2) B-hydroxylacyl-ACP dehydrase (DH) removes H2O --> double bond
(3) Enoyl ACP reductase (ER) uses NADPH to reduce a and B carbons --> saturating double bonds on ACP region of FASN. This process repeats until you're left with palmitate.
1. What enzyme is used to saturate FAs? What must be removed?
2. What is starting material for cholesterol synthesis, ketone synthesis, and fatty acid synthesis?
3. What substrate is common bt ketone and cholesterol synthesis? What enzyme? What is different about the enzymes?
4. What is the committed step of cholesterol biosyn? What 2 rxns does it do? What targets this? What controls rate of synthesis?
5. What happens to the 5-C units that are created? What is released (3) to give the final number of Cs in cholesterol?
9-fatty acyl-CoA desaturase complex --> electrons must be removed.
3. HMG CoA, HMG CoA synthase. Ketone HMG COA synthase is in mitochondria, while cholesterol is made in cytosol.
4. HMG CoA reductase (HMG CoA --> Mevalonate). 2 successive reductions. Statin drugs. SREBP
5. 6 5-C chains are condensed and isomerized to form 5&6C rings.
1 formic acid (HCOOH) and 2 CO2s (5 Cs) are released to give 27-C cholesterol.
1. What are other names for lipid droplets? (5)
2. Describe structure of lipid droplet
3. What does WAT require to store lipids? Why?
4. What is the role of phosphatidic acid?
1. Lipid particles/bodies, adiposomes, eicosasomes, fat globules.
2. Neutral core - TGs and CEs. Outer - phospholipid monolayer + proteins + triglyceride lipases
3. Glucose. Requires glucose --> glycerol 3 P to form TG backbone bc WAT lacks glycerol kinase!!!
4. Phosphatidic acid is the basis for the glycerol backbone of TG in adipose tissue and in the absence of MG/DG.
1. What can happen to FFAs bound to albumin in blood? (4)
2. How do lipids circulate as energy? 3
3. What is the role of catecholamines in lipid metabolism?
4. What does perilipin 1 do?
5. What does HSL do?
1. (1) Energy source in muscle, heart, liver. (2) Liver: oxidation to Ac CoA (3) ketogenesis (4) re-esterification to TAG for storage in liver or secretion as VLDL.
2. Albumin-bound FFA, esterified in TGs in lipoproteins, ketones in special situations
3. (1) Catecholamines binds to B-adregenic receptor --> (2) activates G protein --> (3) activates PKA --> (4) PKA activates Perilipin 1 and hormone-sensitive lipase --> (5) lipolysis.
4. Perilipin 1 relaases CGI-58 activates adipose triglyceride lipase (ATGL) - main lipase of TAGs in adipose tissue. ATGL hydrolyzes TAG to yield FFA + DAG.
5. HSL hydrolyzes DAG --> FFA + MAG(also hydrolyzes cholesteryl + retinyl esters)
1. Why doesn't adipose tissue take up circulating TG in fed state?
2. How might insulin stimulate TG storage in adipose tissue?
3. Why is BAT brown? What protein does it have?
4. Purpose of large, unilocular lipid droplet vs small, multiple lipid droplets in WAT?
1. Inhibitory protein
2. (1) Taking up glucose (2) Tx activation by insulin (3) stimulates lipogenesis in liver and adipose tissue.
3. Lots of mitochondria. UCP-1
4. Prevents rapid lipolysis (efficiency of lipases) in interacting with droplet.
1. What % of ATP in heart is derived from FAs?
2. What type of fibers primarily use fatty acids to generate ATP?
3. What is needed for adipose tissue to uptake FFAs? To lipolyze?
4. How does liver uptake FFAs?
5. What is the glucose-fatty acid cycle? What are key enzymes?
- 1. 70-90
- 2. Type I fibers
- 3. Hormones
- 4. Lipoproteins
- 5. Homeostatic mechanism to control circulating concentrations of glucose and fatty acids such that high [glucose] inhibits FA oxidation and high [FA] inhibits glucose oxidation.
Production of citrate during B-oxidation inhibits PFK-1 (inhibiting glycolysis) promoting fat use over glucose use in starvation.
Generating lots of AcCoA via glycolysis --> citrate --> AcCoA --> MaCoA via ACC. MaCoA inhibits CPT-1 inhibiting B-oxidation
1. What is SREBP? What does it do?
2. Partners? (2)
3. Role of SREBP in cholesterol metabolism?
4. SREBP 1 vs. SREBP2? Do they work together or separately?
5. Role of insulin? Liver? Adipose tissue? Lipogenesis vs. lipolysis? (3)
1. Sterol REgulatory Binding Protein - tx regulator of lipid metabolism.
2. SCAP + INSIG
3. Low cholesterol --> SREBP signaling protein is cleaved goes to nucleus --> activates expression of LDL receptor, HMG CoA reductase, and FA biosynthetic genes.
4. SREBP1 - increases lipogenesis. SREBP2 - increases cholesterol synthesis. They work simultaneously.
5. Insulin activates SREBP1 promoting lipogenesis and secretion of lipids in VLDL form from liver.
- Adipose tissue: insulin binds to receptor -->
- increases SREBP1 --> increases lipogenesis.
Insulin also inhibits B-oxidation, increases glucose/lipid uptake, increases proteins involved in lipid uptake/esterification pathways.
1. What do PPARs stand for? What are they? What are they activated by? (2)
2. What do they do? a, b/d, g
3. Role of arachidonic acid? Role of aspirin?
1. Peroxisomal peripheral activated receptor - nuclear hormone receptors activated by endogenous ligands (i.e., FFAs) and drugs)
- 2. A - activates fat oxidation and fat uptake (CPT-1) promotes lipid storage.
- B/D - activates fat oxidation and inhibits fat uptake
- G - Activates fat uptake and fat storage.
3. ARACHIDONIC ACID - signaling molecules that becomes prostaglandins in inflammatory pathways. Aspirin inhibist arachidonic --> prostaglandins.
1. What is the main function of plasma lipoproteins?
2. What do chylomicrons receive
1. THey keep lipids (primarily TGs and CEs) soluble as they transport them between tissues