Fatty Acid Catabolism Flashcards
Why are triacylglycerols best long-term storage fuel?
FA chains are highly reduced
yield 2x the energy of protein and carbs
don’t affect osmolarity due to hydrophobicity
relatively inert - low risk of undesirable reactions
percent energy derived from beta oxidation in heart and liver
percent energy from fatty acids in TAGs
80% energy from heart and liver
FA contribute to 95% of energy from TAGs
sources of fat
stored
autophagy, dietary fats, fats produced by liver
adipocytes, liver, ovaries, testes, adrenal cortex
Overview of lipid digestion and transport
1) bile salts in small intestine emulsify fats by water soluble enzymes
2) intestinal lipases degrade triacylglycerols/diacylglycerol/monoacylglycerol into free FA and glycerol
3) FA and glycerol taken up into intestinal mucosa and reformed into TAG
4) TAGs + cholesterol + apolipoproteins combined into chylomicrons
5) chylomicrons travel in blood and lymph to tissues
6) Lipoprotein lipase oxidizes FA as fuel or re-esterified for storage
Lipoprotein lipase is activated by
apoC-II in bloodstream to convert TAGs into fatty acid and glycerol
apoC-II dictates dropoff pathway through body
Increasing density of lipid transport molecules (low to high)
chylomicrons (100-500nm diameter), VLDL, LDL, HDL, VHDL
Identification of different densities of molecules by ultra-centrifugation
Apolipoprotein definition
Apolipoproteins are lipid-binding proteins in the blood that are responsible for the transport of triacylglycerols, phospholipids, cholesterol, and cholesteryl esters between organs
Apolipoproteins act as signals to for uptake and metabolism of chylomicron contents
hormones that activate hormone-sensitive lipase
type of signaling
glucagon and epinephrine (mobilization of fatty acids from storage)
G protein coupled receptor signaling via cAMP/PKA
Mobilization of fatty acids from storage pathway
1) Glucagon binds GPCR, G protein, adenylyl cyclase, cAMP
2) PKA active phosphorylates hormone sensitive lipase and perilipin proteins
3) PKA active also triggers dissociation of CGI from perilipin
4) CGI recruits adipose triacylglycerol lipase TAG–> DAG
5) Active hormone sensitive lipase gets access to lipid droplet surface converting DAG –> MAG
6) Monoacylglycerol lipase MAG –> free FA and glycerol
7) up to 10 FA bound by serum albumin in blood for transport
Perilipin
protein that coats lipid droplets and makes them inaccessible and prevents mobilization of fatty acids
CGI-58
comparative gene identification
58 specifically in adipose tissue
Glycerol catabolic pathway
Phosphorylation: Glycerol –> Glycerol-3-phosphate
Enzyme: glycerol kinase (uses ATP)
Oxidation: Glycerol-3-phosphate –> dihydroxyacetone phosphate
Enzyme: glycerol-3-phosphate dehydrogenase (NOT GADPH)
Isomerization: dihydroxyacetone phosphate –> Glyceraldehyde-3-phosphate
Enzyme: triose phosphate isomerase
Continues on to glycolysis
Activation of FAs for transport into mitochondria
12C FA and lower can just enter unassisted
14C FA and higher require acyl-CoA activated
Enzyme: fatty acyl-coA synthase
Location: mitochondria
ATP + Fatty acyl –> Fatty acyl-adenylate (enzyme bound) + 2Pi
Fatty acyl-adenylate + CoA-SH –> Fatty acyl CoA + AMP
Fatty acyl-CoA can also be used to
synthesize longer membrane lipids
in plants fatty acid beta oxidation occurs in
Peroxisomes
carnitine acyltransferase I is inhibited by
malonyl coA (1st intermediate of FA synthesis)
transport of FA into mitochondria
1) carnitine acyltransferase I replaces coA for carnitine on FA
2) complex enters mitochondrial matrix
3) carntine acyltransferase II replaces carnitine for CoA inside matrix
4) carnitine returns across mitochondria matrix in antiport with incoming acyl-carnitines
beta oxidation of 16C saturated FA equation
enzymes in order and their products
ex. 1 palmitoyl-coA –> 8 Acetyl coA, 7 FADH2/7 NADH/7 H+ ( 28 ATP + 7 H2O)
1) acyl-coA dehydrogenase (FAD –> FADH2)
2) enoyl-CoA hydratase (H2O used)
3) beta-hydroxylacyl-CoA dehydrogenase (NAD+ –> NADH + H+)
4) acyl-coA acyltransferase / thiolase (CoA-SH used, produces Acetyl coA for CAC)
equation to calculate products of beta oxidation
4C FA –> 2 Acetyl-CoA, 1 FADH2/NADH/H+, 4(1) ATP, 1 H2O
Beta Oxidation enzymes in bacteria
Short chain FA: 4 enzymes unanchored
Long chain FAs: 3 enzymes (middle has activity of 2/3) anchored to mitochondrial membrane (matrix side)
Beta oxidation of unsaturated FA
enoyl coA hydratase cannot act on unsaturated FA
Two additional enzymes required enoyl-coA isomerase (for mono and polyunsaturated FA) and enoyl-CoA reductase (for polyunsaturated FA only)
As a larger FA is catabolized, each round can require different enzymes
example off 16C FA, 14C, 12C, 3C FA
16C: Palmitate acid
14C: Myristic acid
12C: Lauric acid
3C: Propionate
Odd #C FA beta oxidation pathway
for an odd numbered C FA like propionyl-coA to form succinate to enter CAC
1) Propionyl-coA + biotin + HCO3 –> D-methylmalonyl-coA
propionyl-coA carboxylase
2) D-Methylmalonyl-coA –> L-methylmalonyl-coA
methylmalonyl-coA epimerase
3) L-methylmalonyl-coA + B12 –> succinyl-coA
methylmalonyl-coA mutase
When does beta oxidation occur?
when there is need for energy (Low ATP activates AMPK leading to carnitine shuttle activation)
Carnitine shuttle is point of commitment
What inhibits beta oxidation?
Malonyl-coA inhibits carnitine acetyltransferase I (b/c glucose is available)
High NADH inhibits beta-hydroxylacyl-coA dehydrogenase
High acetyl coA inhibits thiolase (acetyl-coA acyltransferase)
what is AMPK?
AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that is present in all mammalian cells
Beta oxidation enzyme regulator
Stimulates carnitine shuttle
PPARg is
transcription factor that regulates beta oxidation enzymes
Omega Oxidation pathway
Used for medium chain FA like 10C/12C
Location: ER
1) mixed-function oxidase
2) alcohol dehydrogenase
3) aldehyde dehydrogenase
Omega Oxidation pathway
Used for medium chain FA like 10C/12C
Oxidation of FA from end farthest from carbonyl group
Forms double ended carbonyl ends from which acetyl coA can be produced in beta-oxidation
Location: ER in liver and kidney
1) mixed-function oxidase
2) alcohol dehydrogenase
3) aldehyde dehydrogenase
types of ketone bodies
where they are produced
how to are used as energy
acetone, acetoacetate, beta-hydroxybutyrate
acetone produced in low concentrations
produced in the liver and transported to other tissues for conversion to acetyl coA
brain can adapt to use ketones for fuel during starvation
ketone synthesis pathway
1) thiolase
2 acetyl coA –> acetoacetyl-coA
2) HMG coA synthase (liver cytosol)
acetoacetyl-coA –> HMG coA
3) HMG-coA lyase (liver mitochondria)
HMG-coA –> acetoacetate
4) beta-hydroxybutyrate hydrogenase
acetoacetate –> beta-hydroxybutyrate
OR
4) acetoacetate decarboxylase
acetoacetate –> acetone
ketone catabolism pathway
liver cannot use ketone bodies as fuel lacking beta-ketoacyl coA transferase
1) betahydroxybutyrate dehydrogenase
betahydroxybutyrate –> acetoacetate
2) beta-ketoacyl coA transferase
acetoacetate –> acetoacetyl-coA
3) thiolase + CoA-SH
acetoacetyl-coA –> 2 acetyl-coA
