Chapter 16: Lipid Metabolism Flashcards
Why is fat a good storage fuel?
- Fat provides more energy than carbs do and can be easily stored in adipose tissue
- Can be degraded or synthesized
What does acetyl-CoA look like?
What is the fate of glycerol released by TAG hydrolysis?
- Glycerol kinase activates glycerol at the expense of ATP
- Oxidation via glycolysis (5% of energy from fat)
- G3P can be used in TAG or glycerophospholipid synthesis
How is FA-CoA formed? (enzymes and mechanisms)
- ATP + fatty acid <—(Fatty acyl-CoA synthetase)—> Fatty acyl-adenylate
- Fatty acyl-adenylate <—(Fatty acyl-CoA synthetase)—> Fatty acyl-CoA + AMP
Pyrophosphate —(Pyrophosphatase)—> 2 Pi
What is the fate of FA-CoA
- Transported into the mitochondria for oxidation
- Can be used in cytosol to synthesize TAGs or membrane lipids
Draw Carnitine and how it becomes FA carnitine
FA gets attached to -OH
What is beta oxidation? Why is it called that?
- A process which results in the breakdown of Fatty acyl-CoA
- Each pass removes Acetyl moeity as acetyl-CoA
- Stepwise oxidation of C-3 or beta carbon
- Complete oxidation of palmitoyl-CoA is 7 rounds resulting in 8 actyl-CoA, 7 FADH2, 7 NADH
Describe the steps in the carnitine shuttle.
- Carnitine acyl-transferase on outer mito. mem. replaces CoA with carnitine to form Palmitoylcarnitine
- Cartitine acylcarnitine translocase exchanges palmitoylcarnitine for a carnitine
- Conversion of palmitoylcarnitine back to Palmitoyl CoA by Carnitine acyltransferase II releases carnitine
What are the two important functions of carnitine transport cycle?
- Provides mechanism to control flux of FAs toward degradation (matrix) or synth (cytosol)
- Carnitine acyl transferase I is negatively regulated by Malonyl CoA
- Maintains separate pools of CoA
- Cytosolic CoA used anabolicly, Mitochondrial CoA used catabolicly
Draw the steps of beta oxidation. Know the names, substrates, products, and enzymes.
What happens to the NADH, FADH2, Acetyl-CoA from beta oxidation?
- Acetyl-CoA is oxidized into CO2 via citric acid cycle generating NADH and FADH2
- NADH and FADH2 are then used in Respiratory chain
Calculate the number of ATP produced from a complete oxidation of a given fatty acid.
2.5 ATP per NADH
1.5 ATP per FADH2
What are ketone bodies? Know the names and structures.
Acetoacetate:
- Made from 2 acetyl-CoA using β-ketoacyl-CoA thiolase, HMG-CoAsynthase, HMG-CoA lyase
D-β-hydroxybutyrate:
- Made by taking acetoacetate and oxidizing NADH + H+ using the enzyme D-β-hydroxybutyrate dehydrogenase
Know why liver cells only synthesizes ketone bodies but does not use them
- Because the liver does not have β-ketoacyl-CoA transferase which is only found in skeletal and cardiac muscle cells
When is ketogenesis necessary?
- In diabetes/extreme starvation
- Gluconeogenesis depletes citric acid cycle intermediates
- Accumulation of acetyl-CoA
- Leads to production of ketone bodies
Why can ketone bodies only be made in the liver?
- Because the formation of ketone bodies relies on the enzyme HMG-CoA lyase which can only be found in the liver
What happens to D-B-hydrobutyrate in skeletal muscle/cardiac muscle cells?
- Acetyl-CoA will be sent to skeletal muscle/cardiac muscle to be used in the citrate cycle for energy conversion
What is Ketosis? What is Ketoacidosis?
- Ketosis is when the body has a high concentration of acetyl-CoA due to diabetes or extreme starvation
- As acetyl-CoA builds up, ketone bodies accumilate resulting in a drop of pH which is harmful for cells (Ketoacidosis)
Compare fatty acid degradation vs synthesis?
Fatty acid degradation:
- CoA dependent
- FAD/NAD+ dependent
- Multiple enzymes
- Limited by Carnitine transport
Involves: Oxidation, Hydration, Oxidation, and Cleavage
Fatty acid synthesis:
- ACP dependent
- NADPH dependent
- Two enzymes
- limited by Malonyl-CoA synthesis
Involves Condensation, Reduction, Dehydration, and Reduction
What is the role of ACC in FA biosynthesis? What reaction does it catalyze?
- ACC (Acetyl-CoA carboxylase) catalyzes the synthesis of Malonyl-CoA (3C)
- Malonyl CoA serves as the building block for FA synth carried out by FAS
- Irreversible + rate limiting
What is the role of biotin in FA biosynth?
- Mg-ATP, HCO3 —(biotin carboxylase)—> Mg-ADP,Pi
- Biotin —(Acetyl-CoA Carboxylase)—> Carboxybiotin
- Malonyl-CoA —(Carboxyltransferase)—> Acetyl-CoA
- Passes the carboxyl group from HCO3 to acetyl-CoA to make malonyl-CoA
Compare the structures of acetyl-CoA and Malonyl-CoA
What is the rate limiting step of fatty acid synthesis?
Malyonyl-CoA synthesis
What is FAS?
Fatty Acid Synthase is a multifunctional enzyme
Describe the structure of FAS. What order do the complexes work in?
- Homo-dimer
- 7 Complexes
- MAT, ACP, KS, KR, DH, ER,TE
What does each round of FA synthesis require?
KS (condensation)
KR (reduction)
DH (dehydrogenase)
ER (reduction)
Outline the steps of the FA synthesis mechanism
- Acetyl group on MAT gets linked to 2C from malonyl-CoA on ACP via condensation to form β-ketobutyryl
- β-ketobutyryl-ACP is converted to β-hydroxybutyryl-ACP via reduction (β-hydroxybutyryl-ACP)
- β-hydroxybutyryl-ACP undergoes dehydration (butenoyl-ACP) to become Butenoyl-ACP
- Butenoyl-ACP undergoes reduction (butyryl-ACP) to become Butyryl
- Butyryl-ACP can then be extended in subsequent cycles to form long complex FAs
- process will repeat for 7 cycles (Palmitate)
What is the balanced equation of Palmitate synthesis?
8 Acetyl-CoA + 7 ATP + 14 NADPH + 14H+ —–> Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O
Explain the energy expenditure related to palmitate synthesis.
Chemical energy:
- Group transfer potential of ATP (ACC rxn)
- Reducing power of NADPH (two of the FAS rxns)
- ATP used in synthesis of Malonyl-CoA
- NADPH is required to reduce β-keto group and double bond
- Addition energy spent as Acetyl-CoA is transported into mitochondria (citrate shuttle)
How is Acetyl-CoA (acetate) transported into the cytosol?
Citrate shuttle:
- OAA enters citric cycle and exits as citrate
- Citrate is transported out of the mitochondria
- Citrate -> OAA -> Malate -(mitochondria)-> pyruvate -> Mitochondria
- Once in mito, pyruvate and/or malate will be converted to OAA to repeat cycle
How can NADPH be generated?
- Cytosol for animals
- Chloroplast in plants
- Animals: PPP + Malic enzyme
- Plants: photosynthesis
How is FA synthesis regulated?
Allosteric mechanisms:
- Citrate and Palmitoyl-CoA
Covalent modification:
- AMP-activated protein kinase (AMPK)
What stimulates ACC activity?
Protein polymerization:
- Citrate activates via polymerization
- Palmitoyl-CoA deactivates via depolymerization
How is FA synthesis affected by hormonal regulation?
- Insulin signaling stimulates dephosphorylation and polymerization of ACC by activating Protein phosphatase 2A(FA synth)
- Glucagon stimulates phosphorylation and depoly. of ACC through AMP- activated protein kinase(FA breakdown)
What three mechanisms regulate the flux of FA synthesis and degradation?
- Activation of ACC by citrate
- Inhibition of Carnitine acyltransferase I activity by malonyl-CoA
- Inhibition of ACC activity by fatty acyl-CoA
What does cholesterol do?
- Component of cellular membranes
- Precursor for steroid hormones and bile salts
What is the structure of cholesterol like?
- 27C provided by acetate
- 4C rings
- 3 6C rings + 1 5C ring
- Planar and rigid
- Amphipathic
What generally happens in cholesterol synthesis?
- Three acetyl-CoA molecules condense = mevalonate
- Mevalonate is phosphorylated then decarb. to form (5C) Isopentyl diphosphate
3a. 3 molecules of isopentenyl pyrophosphate combined to make Farnesyl pyrophosphate (15C)
3b. Two Farnesyl pyrophosphate combine to make squalene (30C) - Squalene cyclizes to form Cholesterol (20 rxns)
What is the rate limiting step of Cholesterol synthase?
- HMG-CoA + 2NADPH + H+ —(HMG-CoA reductase)—> Mevalonate + 2NADP+ + CoA
Recognize mevalonate and cholesterol.
How is cholesterol synthesis regulated?
- Rate limiting step is HMG-CoA reductase step
- Statin drug will be used to treat cardiovascular disease by inhibiting HMG-CoA reductase
- Cholesterol synthesis must be regulated because of how expensive it is
- Thus synthesis is complimented by diet
How is Cholesterol synthesis hormonally regulated?
Glucagon:
- Stimulates phosphorylation of HMG-CoA reductase causing inactivation or inhibiting cholesterol synth
Insulin:
- Stimulates dephosphorylation of HMG-CoA reductase resulting in activation promoting cholesterol synth
ACAT activation:
- Sequesters cholesterols by making cholesteryl esters
Oxysterol:
- Can inhibit LDLr resulting in uptake of ccholesterol from blood
- Can stimulate HMG-CoA reductase inhibiting synthesis
What are the three main functions of cholesterol
- Cell membranes
- Bile acids
- Storaged in dropets or packaged into lipoproteins and sent to blood
Describe what happens to lipoproteins as the concentration of proteins increases.
As the [protein] increases the density does too, thus HDL has the highest protein% while chylomicrons have the lowest
Describe lipoprotein transportin the body.
- Lipoproteins from diet are put through the circulatory system
- Free fatty acids are absorbed while the lipoproteins are sent to the liver
- HDL precursor sent from liver to peripheral tissue which yields HDL
- HDL can be sent back to the liver, to circulatory system, or excreted as bile acid
How do HDL particles reverse cholesterol transport?
- ApoA-I on HDL is activated by LCAT (lecthin-cholesterol acyltransferase)
- LCAT esterfies cholesterol w/ fatty acid derived from lecithin(phosphatidylcholine)
- Esterified cholesterol is uptaken to HDL particles to return to liver
What are the three important ways cholesterol synthesis can be regulated?
- (diet) Endocytosis of LDL by LDL receptors. carry cholesterol to cholesterol pool where it can meet many fates
- Can be used for amino acids, fatty acids, bile acids, steroid hormones
- (synth) Cholesterol synthesized by liver enzymes from acetyl-CoA leading to cholesterol pool
- Can be inhibited by Statin blocking HMG-CoA reductase
- Low levels of cholesterol will signal increased transcription(SREBP) of LDL receptors sent from ER->Golgi->Cell surface to uptake more cholesterol
What are SREBP’s? What do they do?
- A transcription factor that leads to increase levels of LDL receptors on cell surface = higher rates of LDL endocytosis
What causes atherosclerosis?
- Accumulation of cholesterol in blood vessels
- Oxidized lipoproteins aggregate, monocyte-> macrophage, foam cell ingest lipoproteins, foam cell dies creating plaque
What is Familial Hypercholesterolemia (FH)? What is the genetic cause?
- A disease that leads to misregulation of cholesterol in the body leading to high amounts of LDL leading to cardiovasular disease or atherosclerosis
- The patient has a mutated copy of the gene responsible for FH
- Can be controlled by inhibiting cholesterol biosynthesis which increases LDLr which means more LDL is uptaken
What are statins and how do they work?
- Statins are inhibitors of HMG-CoA reductase and help treat atherosclerosis by lowering serem LDL levels
- Perscribed to heterozygous FH individuals
