L19: Fatty Acid Oxidation and Ketone Metabolism Flashcards
LO1: List the tissues that use fatty acids as a major fuel, and provide an explanation for why brain and RBCs cannot oxidize FAs
Liver, muscle, heart kidney
Brain-FAs can’t cross BBB
RBCs-no mitochondria to complete oxidation
LO2: Name two proteins that have a high affinity for free FA, identify their locations, and describe the role each plays in FA metabolism
Albumin-binds >99% of free FAs in the plasma
Fatty acid binding protein (FABP)- binds intracellular FAs that were able to diffuse across tissue membrane
LO3: Describe the carnitine shuttle and the role it plays in FA metabolism
- used to translocate long chain fatty acyl-CoAs across the IMM (medium and short chain fatty acids can cross without using the shuttle)
- two enzymes to reach mitochondria (CPTI and CPTII), where B-oxidation occurs
- malonyl coA (FA synthesis intermediate) is an inhibitor of CPTI (to prevent futile cycling)
LO4: Calculate the amount of ATP that would result from the total oxidation of palmitic acid (16:0) to CO2 and H2O
129 ATP
- oxidation of 1 molecule of palmitoyl-CoA produces 8 acetyl coA, 7 FADH2, 7 NADH
- 7 FADH2=14 ATP
- 7 NADH=21 ATP
-8 Acetyl CoA=83NADH=24 NADH=72 ATP
=81FADH2=8 FADH2=16 ATP
=8*1GTP=8 GTP=8 ATP
14+21+72+16+8=131 ATP, but 2 ATP are used for the initial activation of FA, so total=129 ATP
LO5: Describe the consequences of a deficiency in either carnitine or in carnitine acyltransferase-I
-carnitine deficiency can result from administration of certain drugs; will reduce efficiency of B-oxidation or prevent it from occurring, so FA couldn’t be mobilized from storage from energy and would build up (fat would have to be drawn from other sources, like protein)
- CPTI is enzyme in OMM; deficiency would prevent passage of fatty acyl-CoA into cell and therefore long chain FAs wouldn’t undergo B-oxidation
- nonketonic hypoglycemia would occur (fats needed to make ketones; blood glucose is used quickly because fat storage can’t be used for energy, ATP isn’t being generated enough for gluconeogenesis, and acetyl-CoA isn’t being provided to activate pyruvate carboxylase/inhibit PDH
LO6: Explain why administration of certain drugs can induce a carnitine deficiency
-low molecular weight organic acids (like valproic acid, used to treat epilepsy) form acyl-carnitines that are excreted (not usable)
LO7: Describe the role of peroxisomes in FA oxidation, and indicate how B-oxidation in peroxisomes differs from B-oxidation in mitochondria
- important in oxidation of very-long chain FAs (>36) and BCFAs
- analogous to mitochondrial B-oxidation, but different isozymes are used and the energy yield is less (FADH2 that forms can’t be used in ATP synthesis, because it is regenerated by O2 with the formation of hydrogen peroxide)
- if FAs generated are between 8-10Cs, they leave the peroxisomes and are taken up by mitochondria, where B-oxidation is completed
LO8: Relate Refsum’s disease and Zellweger syndrome to FA metabolism
REFSUM’S DISEASE
- results from genetic deficiency in alpha-hydroxylase, which normally completes first step of alpha-oxidation pathway for breakdown of BCFAs
- symptoms include retinitis pigmentosa, peripheral neuropathy, hearing loss, ataxia (also can’t break down phytanic acid, which is in dairy products, beef, and lamb)
ZELLWEGER SYNDROME
- results from absence of peroxisomes, which normally break down very-long chain FAs and BCFAs
- VLCFAs and BCFAs accumulate and you can’t synthesize plasmalogens
- fatal within first 2 years (usually within first 6 mos) as extensive brain, kidney, and liver damage occurs
LO9: How are FA oxidation and synthesis coordinated allosterically and hormonally in the liver? What enzymes are targets of regulation?
ALLOSTERIC (malonyl coA and citrate inhibit oxidation, promote FA synthesis)
- malonyl CoA (FA synthesis intermediate) inhibits rate-limiting step of B-oxidation (CPTI)
- citrate (transporter of acetyl-CoA for FA synthesis) activates acetyl-CoA carboxylase (carboxylates acetyl-CoA to form malonyl CoA in FA synthesis) and inhibits fatty acyl-coA
HORMONAL (insulin inhibits oxidation, promotes FA synthesis)
- insulin stimulates synthesis of malonyl CoA (so insulin indirectly inhibits FA oxidation by blocking entry of FAs into mitochondria)
- insulin activates acetyl-CoA carboxylase (carboxylates acetyl-CoA to form malonyl CoA in FA synthesis)
- hormone sensitive lipase activity regulates availability of FAs as fuels for oxidation (is activated by glucagon via cAMP to make substrate available for oxidation)
REGULATED ENZYMES
- CPTI
- acetyl-CoA carboxylase
- HSL
L09: How is FA oxidation regulated in non-lipogenic tissues?
IN MUSCLE- FAs are not synthesized and fatty acid synthase enzyme is not present, but acetyl-CoA carboxylase and malonyl-CoA decarboxylase are present
- exercise acivates AMP-activated protein kinase, phosphorylating acetyl-CoA carboxylase and malonyl-CoA decarboxylase to inhibit ACC and activate MCD
- this results in lower levels of malonyl CoA and higher levels of acetyl-CoA
- CPTI is no longer inhibited and FA oxidation can occur to supply the extra energy needed for exercise
L10: What tissues are involved and what key reactions occur in synthesis and oxidation of ketones?
TISSUES
- liver for synthesis (cellular localization: mitochondria)
- extrahepatic tissues only for oxidation (cellular localization: mitochondria)
KEY REACTIONS OF SYNTHESIS
- thiolase catalyzes condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA
- HMG-CoA synthase condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA
- HMG-CoA lyase catalyzes cleavage that releases acetyl-CoA and acetoacetate
- B-hydroxybutyrate dehydrogenase catalyzes NADH-dependent reduction of acetoacetate to B-hydroxybutyrate
KEY REACTIONS OF OXIDATION
- B-hydroxybutyrate dehydrogenase oxidizes B-hydroxybutyrate to acetoacetate in an NAD+ dependent reaction
- Succinyl-CoA:3-oxo-acid CoA-transferase transfers CoA from succinyl-CoA to acetoacetate, resulting in acetoacetyl-CoA (this enzyme not present in liver, and is induced in brain after a few days of fasting to reduce need for glucose/to spare proteins)
- thiolase cleaves acetoacetyl-CoA y adding CoA, resulting in two molecules of acetyl-CoA
L10: What hormonal state promotes ketone synthesis and how does ketone utilization spare protein?
HORMONAL STATE
-fasting (glucagon) increases ketone synthesis and oxidation so that energy is created for gluconeogenesis, while fed state (insulin) decreases it
-ketone utilization spares protein because if ketones weren’t synthesized, proteins would have to be broken down for energy (in fasted state)
L11: Name the most prevalent lysosomal storage disorder and identify the most effective type of treatment
GAUCHER’S DISEASE
- autosomal recessive, high carrier frequency in Ashkenazi Jews (1 in 10)
- 1 in 50,000-100,000 in US
- B-glucocerebrosidase (cleaves bond in glycolipid metabolism) is deficient, so glucocerebroside is accumulated, liver and spleen enlarge, long bones and pelvis are eroded
TREATMENT
-enzyme replacement therapy using a recombinant glucocerebrosidase given intravenously every 2 weeks
