Lecture 5: Lipid Metabolism Flashcards
What is the major source of carbon for FA synthesis? What are the precursor and end product of FA Synthesis
major source: dietary carbohydrates
FA Synth precursor: Acetyl CoA
FA Synth endproduct: palmitic acid
What are the 3 phases of Fatty Acid Synthesis?
Phase 1: Cytosolic Entry of ACoA
Phase 2: Generation of Malonyl CoA
Phase 3: FA chain formation
FA Synth Phase I Enzymes
- Citrate Synthase
- oxaloacetate and ACoA = citrate
- ATP Citrate Lyase
(+) - glucose, insulin
(-) - PUFA, leptin
FA Synth Phase II Enzymes
- Acetyl CoA carboxylase (adds CO2 to ACoA)
(+) - citrate, insulin
(-) - glucagon, epinephrine, AMP, palmitate, PUFA
- RATE LIMITING ENZYME (needs BIOTIN)
- 2C converted to 3C
What does malonyl CoA regulate?
- inhibits carnitine acyltransferase (FA degradation RLS)
- prevents synthesis and degradation from occurring simultaneously
FA Synth Phase III Enzyme
- Fatty Acid Synthase
(+) - insuling, glucocorticoid hormones
(-) - PUFA
multi-enzyme complex, 2 identical dimers, head to tail
- Acyl Carrier Protein (ACP) moves things between each of the 7 enzymes on one half of the dimer
Fatty Acid Synthesis Reactions
- Condensation (acetyl and malonyl groups)
- Reduction (ketoacyl –> hydroxyl)
- Dehydration (hydroxyl –> trans-enone)
- Reduction (4 chain fatty acyl group)
repeats 6 more times
Regulation of Fatty Acid Synthase (allosteric and induction/repression at gene level)
Allosteric:
(+) - phosphorylated sugars
Gene Level:
(+) - insulin, glucocorticoid hormones, hi carb/low fat
(-) - high fat diets, PUFA
Synthesis of Longer Chain FA and carbon donors
- elongation in SMOOTH ENDOPLASMIC RETICULUM
- lengthened 2 carbons at time (NADPH reducing power)
SER –> Malonyl CoA (carbon donor)
Mitochondria –> Acetyl CoA (carbon donor)
FA Desaturation
- Acyl CoA Desaturases (4 desaturases - 4,5,6,9)
cannot introduce DB past carbon 9 and 10
- require omega 3 and 6 fatty acids (Essential FA)
Essential Fatty Acids (2) and what they can make
Omega 6: Linoleic Acid (18:2)
- can make arachidonic acid (20:4)
- precursors for EICOSANOIDS
Omega 3: Linolenic Acid (18:3)
- can make EPA (20:5) and DHA (22:6)
TAGs and Energy Storage
- TAGS contain 6.75 times as much energy as glycogen (carbs)
normal man: 40 Cal glucose, 600 Cal glycogen, 24,000 Cal protien, 100,000 Cal TAGs
3 main sources of TAGs
- Dietary TAGs (intestinal processing)
2. De Novo TAGs (hepatocytes and adipocytes)
Intestinal TAG Synthesis
- dietary TAGS –> MAG and FFA in intestinal lumen
- MAG used as backbone (2 fatty acyl CoA added) in order to make TAG
- TAGs packaged w/apolipoproteins and other lipids to make Chylomicrons (released to lymphatic system and enter blood)
Hepatocyte TAG Synthesis and enzymes
enzymes: fatty acid acyl synthetase, G3P dehydrogenase, glycerol kinase
- glucose/glycerol form G3P (used as TAG backbone)
- FFA (liver) added to G3P to form TAGs
- packaged w/apolipoproteins/lipids to make VLDL (released into bloodstream)
Adipocyte TAG synthesis and enzymes
enzymes: G3P dehydrogenase, capillary lipoprotein lipase (+: insulin)
- glucose to G3P (backbone)
- FFA (chylomicrons/VLDL) added to G3P to make TAGs
4 major lipases in TAG breakdown
- adipose triglyceride lipase (ATGL)
- TAG –> DAG
- hormone sensitive lipase (HSL)
- DAG –> MAG
- lipoproteinlipase (LPL)
- DAG –> MAG
- monoacylglycerol lipase (MAG Lipase)
- MAG –> DAG
Molecules that regulate HSL
- Hunger and Exercise (phosphorylate HSL - PKA)
- Hunger (+) –> glucagon
- Exercise (+) –> epinephrine
- Fed Status (dephosphorylate HSL - protein phosph 1)
- High carb meal (-) –> insulin
What is a perilipin and what does it do?
- family of proteins, coat lipid droplets in adipocytes/muscle cells
- REGULATE LIPOLYSIS (control physical access to HSL)
- Overexpression: inhibit lipolysis and knock-out has converse effect
- obesity treatment target
Fatty Acid Activation Phase I (Mitochondrial Transport) and enzymes
- LCFA/VLCFA need to be actively transported into mito
enzymes: fatty acyl CoA synthetase, Carnitine palmitoyltransferase I (CPT1 –> RLS), Carnitine-acylcarnitine translocase (CACT), Carnitine palmitoyltransferase II (CPT II)
Mitochondrial Membrane permeability to Fatty Acids
Outer Mito Membrane - not permeable to FA
- FA to FA CoA
Inner Mito Membrane - not permeable to FA CoA
- FA CoA to FA carnitine
- CPT1 adds carnitine (rate limiting enzyme)
- CPT2 removes carnitine
- CACT moves carnitine across inner mito membrane
What is the rate limiting enzyme of Fatty Acid Oxidation?
carnitine palmitoyltransferase I
(-) - malonyl CoA
What are the 4 steps of B oxidation of Fatty Acids and what do they generate?
steps: oxidation, hydration, oxidation, thiolysis
1st oxidation enzyme: Acyl CoA Dehydrogenase (ACAD)
- four types: short, medium, long, very long
- MCAD is the most common defective
generates: Acetyl-CoA (8), NADH (7), FADH2 (7)
How much energy does NADH, FADH2, and Acetyl CoA produce?
NADH –> 2.5 ATP per mol
FADH2 –> 1.5 ATP per mol
Acetyl CoA –> 10 ATP per mol
Beta Oxidation of odd numbered FAs
- metabolized until Propionyl CoA (3C)
- Propionyl CoA Carboxylase
- ATP, generates Methylmalony CoA
- Methylmalonyl CoA Mutase
- generates Succinyl CoA
Succinyl CoA enters TCA cycle
Beta Oxidation of Unsaturated FAs
- metabolized until unsaturation reached
- Reductase removes DB, Isomerase moves disruptive bond
MCAD Deficiency
- impairs breakdown of medium chain fatty acids (MCFA)
- leads to secondary carnitine deficiency (excessive MCA carnitines in urine)
- C8 FA accumulates in liver, poisonous, disrupts urea cycle, inc. ammonia lvls
patient depends on GLUCOSE as energy source
treatment (preventative) –> avoid fasting, situations that rely on FA Beta Oxidation
What are ketone bodies and what are examples?
- water soluble, acidic (produced in Liver)
ex: Acetoacetate –> B-Hydroxybutyrate and Acetone
Fuel Supply during fasting and starvation
- first few hours: blood glucose, then glycogen, then gluconeogenesis (liver)
- 1 day fasting: TAGs (adipose); FFA –> B oxidation
- 3 days fasting: ketone bodies and muscle proteins broken down
- 1-2 weeks starvation: brain use ketone bodies
- 2-3 weeks starvation: TAGs depleted, proteins main source
Ketoacidosis during Starvation and Diabetes
- pathological occurs: glucagon/insulin ratio increased, favoring FA breakdown
- inc. gluconeogenesis (reduced oxaloacetate
- inc. ketone bodies
- occurs during fasting, pregnancy, in babies, prolonged exercise, ketogenic diet
ketone bodies lower blood pH (acidosis), inc. excretion
acetone exhaled from breath (fruity)
