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Flashcards in Lipid Metabolism Deck (87)
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Explain the mobilization of fatty acids.

1. hormone binds receptor
2. receptor sends signal (cAMP) to activate PKA
3. PKA phosphorylates hormone sensitive lipase
4. PKA phosphorylates perilipin
5. Perilipin releases CGI that activates ATGL. ATGL removes 1st fatty acid. HSL removes 2nd, monoacylglycerol lipase removes 3rd.
6. fatty acids released
7. fatty acids binds albumin (blood stream)
8. fatty acid transporter takes up fatty acid
9. fatty acid oxidized (beta oxidation) form ATP an CO2


What is Perilipin and what does Perilipin do?

- Perielipin is a protein that coats lipid droplets.
Protective coating until phosphorylated
- releases CGI protein that activates ATGL to remove 1st fatty acid of TAG


What happens first to cytoplasmic fatty acids in FA oxidation?

- fatty acids converted to fatty acyl-CoA
-by acyl CoA synthetase
- producing 2Pi


Why do you need to invest 2 high energy phosphates?

- you need ATP to create a high energy bond and produce 2 Pi


Why are free fatty acids damaging and how is this solved in fatty acid oxidation?

- detergent activity of hydrophobic tail and hydrophillic head can denature proteins and dentaure membranes
- by tying it off with the thioester group (-SH) from the CoA, this prevents denaturing activity


How are fatty acids transported into the mitochondria?

-If less than 12 than no transporter
- if greater than 14 carnitine shuttle


Enzyme involved in fatty acyl group transferred to carnitine.

- carnitine acyltransferase I (CAT1)


Enzyme involved in fatty acyl-carnitine to enter mitochondria

- acyl-carnitine/carnitine transporter


Enzyme involved in fatty acyl-CoA regeneration

- carnitine acyltransferase II
- then the carnitine is recycled


Where is fatty acyl-carnitine formed at?

-formed outer membrane of intermembrane space of mitochondria


How does fatty acyl-carnitine move into the matrix?

- facilitated diffusion


Carnitine acyltransferase I is inhibited by ______

malonyl CoA
- inhibition prevents the simultaneous synthesis and degradation of fatty acids
- keeps the fatty acids out of mitochondria
- keep it out to make fat
- bring into mitochondria to burn fat


Why do you need a shuttle for fatty acids?

- CoA is big polar, very hard to get across membrane
- carnitine is small


Where does oxidation of fatty acids occur?



What are the three complete stages of fatty acid oxidation

1. beta oxidation
2. acetyl CoA oxidized in citric acid cycle
3. NADH and FADH2 donate e- to mitochondrial respiratory chain


What is the final electron acceptor?

- huge affinity for e-


4 steps of beta oxidation

1. dehydration of fatty acyl CoA
2. hydration of enoyl CoA
3. dehydration of hydroxacyl CoA
4. cleavage of betaketoacylCoA


Beta oxidation: Step 1

- dehydration of fatty acyl-CoA
- enzyme: acyl-CoA dehydrogenase
- FADH2 produced
- enoylCoA produced
- alkane to alkene


Beta oxidation: Step 2

- hydration of enoyl-CoA (of the trans //
-enzyme: enoyl-CoA hydratase
- produce hydroxacyl-CoA


Beta oxidation: Step 3

- dehydration of hydroxyacyl-CoA
- enzyme: beta hydroxyacyl-CoA dehydrogenase
- NADH + H+ produced
- betaketoacyl-CoA produced


Beta oxidation: Step 4

- cleavage of beta ketoacyl-CoA
- enzyme: acyl-CoA acetyltransferase/thiolase
-add CoA-SH
- acetyl CoA produced
- fatty acyl-CoA (minus 2C) produced


How much ATP is produced from beta oxidation?

1 NADH = 2.5 ATP
1 FADH2 = 1.5 ATP
1 Acetyl-CoA = 10 ATP
(10ATP comes from one TCA cycle of acetylCoA)


Special cases of oxidation:
unsaturated FA - cis bond

- beta oxidation works on trans double bonds only
- in food FA are in cis
- they must be rearranged and then isomerized


Special cases of oxidation:
polyunsaturated FA - two double bonds

- convert poly-unsat FA to mono-unsaturated FA (cis) then to trans


Special cases of oxidation: odd number carbons

- metabolized in a different pathway
- beta oxidation must work on even number carbons
- beta oxidation to C3CoA then Vit B12 will add a carbon so you end up in the middle of the TCA cycle as succinylCoA (C4)


What is the major source of energy for daily activity?

lipid metabolism
~400,000kJ compared to free glucose 50kJ


Fatty acid biosynthesis is a (oxidation/reduction) reaction?



When does fatty acid biosynthesis occur?

- TCA cycle shuts down when there is a lot of energy
- acetyl CoA will not go through TCA but converted to malonyl CoA (intermediate)


When the citric acid cycle is stopped... what happens to citrate

- citrate is converted to acetyl-CoA
- enzyme: citrate lyase


When the citric acid cycle is stopped... malonyl-CoA is formed from ____ + _____.

- acetyl CoA and HCO3
- enzyme: acetyl-CoA carboxylase reaction


What components make up acetyl CoA carboxylase?

- biotin carrier protein
- biotin carboxylase
- transcarboxylase


What is the biotin carrier protein?

- carrier of biotin cofactor on ACC


What is biotin carboxylase role?

- activates CO2
- binds CO2 and biotin together
- part of ACC


What is the transcarboxylase role?

- transfers CO2 from biotin to acetyl CoA
- part of ACC


How does biotin aid the production of malonyl coA

- biotin is attached to the carrier protein on acetyl coA carboxylase
- biotin protein has a long arm that acts as a conveyor belt to efficiently swing back and forth to process the two metabolites in close proximity
- involves different enzymes


What are the 4 repeating steps of fatty acid biosynthesis?

- condensation
- reduction
- dehydration
- reduction


What occurs in condensation in the fatty acid biosynthesis cycle?

- condensation of the saturated acyl groups (the substrates for condensation) activated with malonyl CoA
- growing acyl group
- carbon dioxide lost (the one ACC added to malonyl group)
-enzyme: ketoacyl-synthase (KS)


What occurs in 1st reduction in the fatty acid biosynthesis cycle?

- reduction of the beta-keto to alcohol
- enzyme: ketoacyl-reductase (KR)


What occurs in dehydration in the fatty acid biosynthesis cycle?

- water is eliminated to form a double bond
- ane to ene
- enzyme: hydroxyacyl dehydratase (DH)


What occurs in 2nd reduction in the fatty acid biosynthesis cycle?

- reduction of C//C to form saturated (-ane) acyl group
- lengthened by 2 carbons
- NADPH + H+ to NADP
- enzyme: enoyl-reductase (ER)



- used in fatty acid biosynthesis in the reduction reactions
- the phosphate on the ribose are for anabolic reactions (catabolic does not use phosphate - NADH)



- used in fatty acid biosynthesis in the reduction reactions
- the phosphate on the ribose are for anabolic reactions (catabolic does not use phosphate - NADH)


What is ACP?

acyl-carrier protein
- has phosphopantetheine arm
- flexible arm


What is ACP?

acyl-carrier protein
- has phosphopantetheine arm
- flexible arm


What is fatty acyl CoA desaturase?
What is involved in this reaction?

- it introduces a C//C by oxidative reaction
- converts saturated fatty acyl-CoA to monounsaturated fatty acyl-CoA
-involves oxygen and release of 2 water
-NADPH undergoes electron oxidation to NADP+


What are the 3 regulation methods/levels of control?

- rapid
- slow/moderate
- gradual/adaptive


Rapid regulation

- cellular regulation of enzymes
- allosteric


Example of rapid regulation

citrate regulates metabolism of fatty acids


What signal does citrate send?

- citrate signals lots of energy in mitochondria (indicating lots of energy)
-therefore you do not need anaerobic glycolysis
- citrate is therefore an allosteric inhibitor and activates
- "+" Acetyl-CoA Carboxylase (ACC) to make malonyl CoA (for biosynthesis pathway)


Slow/moderate regulation

- hormonal regulation
- phosphorylation and dephosphorylation


Example of slow/moderate regulation.

- glucagon and insulin triggers signal cascade


What does the glucagon signal do?

- glucagon is signalled when energy is needed
- this activates "+" PKA to phosphorylate and inhibit "-" ACC


What does insulin signal do?

- insulin does the opposite to glucagon and indicates excess energy
- it will dephosphorylate and reactivate "+" anabolic enzyme ACC


Gradual/adaptive regulation

- change in gene expression
- transcription factors
- upregulate biosynthesis of enzymes (make more enzymes to make more fat)


Example of gradual/adaptive regulation.

- high fat diet triggers beta oxidation enzyme synthesis


What molecule does high fat diet involve to trigger beta oxidation enzyme synthesis?

- insulin


What does insulin signalling in gradual/adaptive regulation do?

- insulin signals increased synthesis of FAS
- this will activate DNA to make more mRNA


What is the committed step in fatty acid oxidation regulation? How does this affect FFA biosynthesis vs FFA oxidation?

- the transfer of fatty acids into the mitochondria
- FFA biosynthesis inhibits the IMPORT and therefore inhibits the oxidation of FFA at CAT-1 (if there is anabolism then there is no catabolism)


What happens after the committed step in FA oxidation? How does inhibition work here?

- after the import of FFA into the mitochondria
- FA are broken down by beta oxidation


How is FA oxidation inhibited if there already is FFA inside the mitochondria?

- primary inhibition is transport into mitoch. but if you already have fat in mitoch. the 1st product of biosynthesis (malonyl-CoA) inhibits the 1st step into mitoch. CAT1 for oxidation.
-malonyl CoA inhibits carnitine acyltransferase I


What are the 2 feedback inhibitions in the regulation of FA oxidation?

- high [NADH]/[NAD+] inhibits beta-hydroxyacyl-CoA dehydrogenase
- acetyl-CoA inhibits thiolase


What is the role of ACC step in fatty acid biosynthesis?

- polymeric, active form of ACC (dephosphorylation) catalyzes the committed step - rate limiting
(active in nonphosphorylated form)
- acetylCoA to form Malonyl CoA
- carboxybiotin involved )(ecycled to biotin)


Why is ACC step highly regulated?

- it is the most important step - it is the committed step


How is ACC regulated (inhibited by)?

- glucagon
- epinephrine
- Palmitoyl-CoA (end product)
- AMPK (trigger phorphorylation/inactivation)


What activates ACC in FA biosynthesis

- insulin
- citrate: citrate in cytosol represents precurser of acetylCoA - indicating energy is high in the cell therefore it can store in the fat


What is the role of insulin in FA metabolism?

- move glucose out of the blood for storage (as glycogen or fat) or anabolism
- high blood glucose, increase insulin
- dephosphorylation


What is the role of glucagon in FA metabolism?

- low blood glucose
- increase glucagon
- phosphorylation of anabolic enzymes (ACC) via PKA


How does the triacylglycerol assembly begin?

the formation of G3P (glycerol 3 phosphate) via 2 ways
- from dihydroxyacetone phosphate (DHAP) - enzyme: glycerol 3 phosphate dehydrogenase
- from glycerol - enzyme: glycerol kinase


What is the major contributor (source) to form TAG?

- dihydroxyacetone phosphate (DHAP)


What is phospholipid biosynthesis?

- G3P: glycerol 3 phosphate forms phosphatidic acid


Where is TAG synthesized?

- made in the liver
- but needs to be transported out via lipoproteins to move the fat so that the liver does not become too fatty and toxic


Lipoprotein lipase transport.

- LPL FFA from the blood is transported to adipose tissues via glycerol
- glycerol -> glycerol 3 phosphate -> TAG


What is opposite to the glycerol lipoprotein lipase. movement to the adipose?

-TAG from adipose -> glycerol -> blood for energy
- hormone sensitive lipase


When are ketone bodies produced?

- at low glucose levels
- minimal oxidation of Acetyl CoA
- not enough OAA,
- recycling of CoA
-Acetyl-CoA is converted to ketone bodies (or cholesterol biosynthesis)


The role of acetone.

- exhaled (bad breath)
- helps with body diagnosis for low sugar - i.e. diabetic / fasting
- converted from acetoacetate


Can the liver utilize ketone bodies?

no, it lacks transferase to convert


What are ketone bodies?

lipid droplets including
- acetone, acetoacetate, D-b-hydroxybutyrate
- acetone is exhaled
- other two are transported as sources for energy for heart, skeletal muscle, kidney and brain (but brain only in starvation cuz it prefers glucose)


2 Acetyl-CoA and D b-hydroxybutyrate

convert back and forth (ketone body formation / last step of beta oxidation)
- involves thiolase
- ketone body formed in liver
then transported out and used for energy via beta oxidation


The liver
it's enzymes ___

major metabolic centre of the human body
- enzymes detoxify toxic compounds


Where do nutrients go first and how?

1st stop: liver
via portal vein from small intestines


Liver as a metabolic buffer 3 ways

- glucose to glycogen or FA (when too high glucose)
- release glucose by glycogen phosphorylation (glycogen to glucose) or gluconeogenesis (when too low glucose)
- releasing ketone bodies as alternative fuel


Enzyme expression in liver

- enzymes change expression to optimize nutrients of diet


Metabolic pathway of glucose 6 phosphate in liver: 5 ways

1. dephosphorylated back to glucose (replenish blood glucose)
2. used to make glycogen for later
3. enter glycolysis with acetyl coA - TCA to make ATP for liver's energy needs
4. enter glycolysis with acetyl coA - make FA and cholesterol
5. enter pentose-PO4 pathway - make NADPH and nucleotides ribose


Metabolism of Fatty Acids in the liver

1. FA for liver membranes / repair
2. FA is primary oxidative fuel in liver (beta oxidation, TCA, oxidative phosphorylation)
3. Excess acetyl-CoA to make ketone bodies (fuels other tissues), cholesterol, bile, steroid h.
4. Liver can synthesize TAG from FA to transport to adipose tissue for storage or other tissues for energy (free FA or plasma lipoproteins)


Purpose of adipose tissue

- store fatty acids (glucose to FA)
- as triacylglycerols
- which accumulate as lipid droplets in cytoplasm
- can release FA to serve as fuel for other tissues


What do adipose tissues respond to?

hormone signal (epinephrine and insulin)
- indicate store or hydrolyze to use for energy


Three types of fat

1. good - subcutaneous
2. visceral / abdominal (bad)
3. ectopic - i.e. liver/ muscle (bad)