Flashcards in RR - Lipid Metabolism I Deck (97):
Fatty acid synthesis begins in the ...?
Mitochondria with the formation of CITRATE as a 2-carbon transporter (acetyl CoA shuttle to cytoplasm).
Acetyl CoA carboxylase provides ...?
Malonyl CoA to be used by the multienzyme complex, the fatty acid synthase.
Regulation of fatty acid synthesis occurs at ...?
Acetyl CoA CARBOXYLASE - Controlled by:
Fatty acid synthesis - Step 1:
The citrate shuttle transports acetyl CoA generated in the mitochondrion to the cytosol.
--> Acetyl CoA + OAA undergo an IRREVERSIBLE CONDENSATION by citrate synthase to form CITRATE, which is transported across the mitochondrial membrane into the cytosol.
Why must acetyl CoA be irreversibly condensed with OAA to form citrate?
Because acetyl CoA CANNOT cross the mitochondrial membrane.
Fatty acid synthesis - Step 2:
Citrate is converted back to acetyl CoA and OAA by citrate LYASE, in a reaction that required ATP.
Citrate lyase is enhanced by ...?
Fatty acid synthesis - Step 3:
Acetyl CoA --> Malonyl-CoA, by acetyl CoA carboxylase in an IRREVERSIBLE rate-limiting reaction that consumes ATP + REQUIRES BIOTIN.
Malonyl CoA inhibits:
Carnitine acyltransferase I --> Preventing movement of newly synthesized fatty acid across the inner mitochondrial membrane into the matrix, where fatty acids undergo β-oxidation (futile cycling is thereby avoided).
Fatty acid synthesis - Step 4:
Fatty acid SYNTHASE initiates and elongates the fatty acid chain in a cyclical reaction sequence.
Fatty acid synthesis - What is the final product?
Palmitate, a 16-carbon saturated fatty acid.
OAA from citrate cleavage is converted to ...?
Malate is further converted to ...?
Pyruvate by MALIC ENZYME, producing 1 NADPH.
NADPH is required for the synthesis of ...?
Palmitate + elongation of fatty acids.
NADPH is produce in the cytosol by ...?
Malic enzyme and the pentose phosphate pathway, which is the primary source.
Conversion of fatty acids to triacylglycerols in liver and adipose tissue - Step 1:
In the fed state, fatty acids synthesized in the liver or released from chylomicrons and VLDL by capillary lipoprotein lipase, are used to synthesize triacylglycerols in liver and in adipose tissue.
Conversion of fatty acids to triacylglycerols in liver and adipose tissue - Step 2:
1. Glycerol 3-P is derived from DHAP during glycolysis or from the conversion of glycerol into glycerol 3-P by liver glycerol kinase.
2. Glycerol 3-P is the carbohydrate intermediate that is used to synthesize triacylglycerol.
3. Decreasing the intake of carbohydrates is the most effective way of decreasing the serum concentration of triacylglycerol.
Conversion of fatty acids to triacylglycerols in liver and adipose tissue - Step 3:
Newly synthesized fatty acids or those derived from hydrolysis of chylomicrons and VLDL are converted into fatty acyl CoA by fatty acyl CoA synthetase.
Conversion of fatty acids to triacylglycerols in liver and adipose tissue - Step 4:
Addition of 3 fatty acyl CoAs to glycerol 3-P produces triacylglycerol (TG) in the liver.
Conversion of fatty acids to triacylglycerols in liver and adipose tissue - Step 5:
Liver triacylglycerols are packaged into VLDL, which is stored in the liver and transports newly synthesized lipids through the bloodstream to peripheral tissues.
Conversion of fatty acids to triacylglycerols in liver and adipose tissue - Step 6:
Synthesis and storage of triacylglycerol in adipose tissue require INSULIN-mediated uptake of glucose --> Glycolysis and production of glycerol 3-P --> Converted to TG by the addition of 3 fatty acyl CoAs.
Insulin does what to hormone-sensitive lipase?
Inhibits hormone-sensitive lipase, which allow adipose cells to accumulate triacylglycerol for storage during fed state.
Epinephrine and GH do what to hormone-sensitive lipase?
ACTIVATE hormone-sensitive lipase during the fasting state.
Formation of malonyl CoA from acetyl CoA - the IRREVERSIBLE regulated step in fatty acid synthesis, is controlled by 2 mechanisms:
1. Allosteric regulation of acetyl CoA carboxylase:
--> Stimulation by citrate ensures that fatty acid synthesis proceeds in the fed state.
--> End-product inhibition by palmitate downregulates synthesis when there is an excess of FFAs.
2. Cycling between active and inactive forms of acetyl CoA carboxylase:
--> High AMP level (low energy charge) inhibits fatty acid synthesis by phosphorylation of acetyl CoA carboxylase, which INACTIVATES the enzyme.
--> Glucagon and epinephrine (fasting state) inhibit acetyl CoA carboxylase by phosphorylation (by protein kinase); insulin (fed state) activates the enzyme by dephosphorylation (by phosphatase).
Inhibition of acetyl CoA carboxylase enhances the ...?
OXIDATION of fatty acids, because malonyl CoA is NO LONGER present to inhibit CARNITINE ACYLTRANSFERASE I.
Fatty acid and triacylglycerol synthesis occurs in the ...?
CYTOPLASM, BUT its precursor acetyl CoA, is formed in the mitochondrial matrix.
Fatty acid and TG synthesis - Synthesis of longer-chain fatty acids and unsaturated fatty acids:
Chain-lengthening systems in the endoplasmic reticulum and mt convert palmitate (16 carbons) to stearate (18 carbons) and other longer saturated fatty acids.
Why does fat synthesis happen in the cytosol?
To ensure bioavailability of NADPH from pentose phosphate pathway.
Adipose tissue doe NOT contain glycerol kinase, so ...?
The glycerol backbone of TGs must come from glycolysis.
DESATURATION of fatty acids to produce UNsaturated fatty acids occurs in the ...?
Endoplasmic reticulum in a complex process that requires O2 either NADH or NADPH.
UNsaturated fatty acid are stored in ...?
TGs, at the carbon 2 position.
Unsaturated fatty acids are used in ...?
Making phosphoglycerides for cell membranes.
Fatty acid desaturase introduces ...?
Double bonds at the carbon 9 position.
Why linolenic and linoleic acids are the essential fatty acids?
Because fatty acid desaturase cannot create double bonds beyond carbon 9 preventing synthesis of linoleic and linolenic acid.
Essential fatty acid deficiency:
Dermatitis + Poor wound healing.
An excess of fatty acids in the liver over the capacity for oxidation (eg chronic alcoholics) results in ...?
Resynthesis of TG and storage in fat droplets, which produces a FATTY LIVER.
Fatty acids are mobilized in the fasting state by activating ...?
Long-chain fatty acids are shuttled into the mitochondrial matrix by formation of ...?
Acyl-carnitine esters - Catalyzed by carnitine acyltransferase.
Beta oxidation of fatty acids consists of a repeating sequence of ...?
4 enzymes to produce acetyl CoA.
Is fatty oxidation regulated in the liver?
What is the only point of regulation of fat oxidation?
The hormone-sensitive lipase in the fat cell.
Odd-chain fatty acids undergo normal beta oxidation until ...?
Propionyl CoA is produced.
Propionyl CoA is converted by normal beta-oxidation to ...?
Methylmalonyl CoA and then to succinyl CoA.
UNsaturated fatty acids enter the normal beta-oxidation pathway at the ...?
Deficiencies in fatty acid oxidation produce ...?
Fatty acid oxidation - Step 1:
1. Mobilization of stored fatty acids from adipose tissue (lipolysis).
2. Hormone-sensitive lipases in adipose tissue HYDROLYZE FFAs + glycerol from TGs stored in adipose tissue.
What is the fate of glycerol releaseed during lipolysis?
It is transported to the LIVER, phosphorylated into glycerol 3-P by glycerol kinase, and used as a substrate for GLUCONEOGENESIS.
Hormone-sensitive lipase is activated by ...?
--> Promote lipolysis.
Fatty acid oxidation - Step 2:
FFAs released from adipose tissue are carried in the bloodstream bound to serum albumin.
Fatty acid oxidation - Step 3:
1. The fatty acids are delivered to ALL tissues (eg liver, skeletal muscle, heart, kidney), except for brain and RBCs.
2. The fatty acids dissociate from the albumin and are transported into cells, where they are acetylated by fatty acyl CoA synthetase in the cytosol, forming fatty acyl CoAs.
Fatty acid oxidation - Step 4:
The carnitine shuttle transports long-chain (>14-carbon) acetylated fatty acids across the INNER mitochondrial membrane.
Role of carnitine acyltransferase I:
Rate-limiting reaction - On the OUTER surface of the INNER mt membrane removes the fatty acyl group from fatty acyl CoA and transfers it to carnitine to form fatty acyl carnitine.
Role of carnitine acyltransferase II:
On the INNER surface of the INNER mt membrane restores fatty acyl CoA as fast as it is consumed.
Medium-chain fatty acids are consumed ...?
Directly by the mitochondria because they do NOT depend on the carnitine shuttle.
Medium-chain TGs are an effective dietary treatment for ...?
An INFANT with CARNITINE DEFICIENCY.
--> They also SPARE GLUCOSE for the brain + RBCs and serve as a fuel for all other tissues.
Fatty oxidation - Step 5:
The oxidation system consists of 4 enzymes that act sequentially to yield a fatty acyl CoA that is 2 carbons shorter than the original.
+ Acetyl CoA, NADH, FADH2.
End product of even-chain saturated fatty acids.
Which substance coats the lipid droplets in adipose cell in the unstimulated state?
How is perilipin removed?
Phosphorylation of perilipin removes it from the lipid droplet so that the activated hormone-sensitive lipase can act to mobilize FFAs.
Action of insulin on lipolysis?
Activates protein PHOSPHATASE --> Inhibits lipolysis by converting hormone-sensitive lipase into an inactive dephosphorylated form.
Role of glucocorticoids, GH, and thyroid hormone on lipolysis?
Induction of SYNTHESIS of hormone-sensitive lipase --> Provides more enzyme available for activation (ie activation by these hormones is INDIRECT).
Carnitine acyltransferase I is inhibited allosterically ...?
By malonyl CoA to prevent the unintended OXIDATION of newly synthesized PALMITATE.
Malonyl CoA is the ...?
PRECURSOR used in fat synthesis - Its concentration reflects the active synthesis of palmitate.
Total energy yield from oxidation of long-chain fatty acids (eg palmitate, stearate)?
More than 100ATP per molecule.
Malonyl CoA is absent in the ...?
Fasting state when fatty acids are being actively oxidized.
Fatty acid synthesis vs oxidation - Primary tissues:
Oxidation: Liver, muscle.
Fatty acid synthesis vs oxidation - Carriers of acetyl and acyl groups:
Synthesis: Citrate (mt --> cytosol).
Oxidation: Carnitine (cytosol --> mt).
Fatty acid synthesis vs oxidation - Redox coenzyme:
Oxidation: NAD+, FAD.
Fatty acid synthesis vs oxidation - Allosterically regulated enzyme:
Synthesis: Acetyl CoA carboxylase (citrate stimulates; excess fatty acids inhibit).
Oxidation: Carnitine acyltransferase I (malonyl CoA inhibits).
Ketone body synthesis serves as an ...?
Overflow pathway during EXCESSIVE fatty acid supply (usually from accelerated mobilization).
Ketone body synthesis occurs in the ...?
Mt MATRIX during the fasting state when excessive beta-oxidation of fatty acids results in excess amounts of acetyl CoA.
3 conditions associated with an excess production of ketone bodies:
The usual test for measuring ketone bodies in serum or urine ...?
Nitroprusside reaction - Only detects acetoacetate and acetone - A spontaneous decomposition product of acetoacetate.
Rate-limiting enzyme in ketone body synthesis:
HMG CoA synthase.
Why β-hydrobutyrate is the primary ketoacid that develops in alcoholics?
Because of increased production of NADH in alcohol metabolism --> NADH forces the reaction in the direction of β-hydroxybutyrate - NOT detected by standard lab tests.
Why the fruity odor in DKA?
Due to acetone production from acetoacetate.
Do ketone bodies require special transport system for entry into the cell and into the mt?
NO - Ketone bodies are short-chained fatty acids.
Conversion of β-hydrobutyrate back into acetoacetate generates ...?
NADH, which enters the ETC.
Can the liver use ketones for fuel?
NO - It lacks the enzyme succinyl CoA: acetoacetate CoA transferase --> Necessary to convert acetoacetate into acetyl CoA.
Odd-numbered fatty acids undergo oxidation by the SAME pathway as saturated fatty acids, except ...?
That propionyl CoA (3 carbons) remains after the final cycle.
What is the fate of the propionyl CoA that remains after odd-chained fatty acid oxidation?
It is converted first to methylmalonyl CoA and then to succinyl CoA, a CAC intermediate that enters the gluconeogenic pathway.
Role of B12 in the conversion of propionyl CoA to methylmalonyl CoA?
It is a cofactor for one of the enzymes (methylmalonyl CoA MUTASE) in this pathway.
MAJOR difference between odd-chain fatty acid metabolism and even-chain fatty acid metabolism?
Succinyl CoA is a substrate for gluconeogenesis, and acetyl CoA is NOT.
Catabolism of which amino acids ALSO produce propionyl CoA?
Fate of very long fatty acids (20-26C)?
PEROXISOMAL oxidation of very-long-chain fatty acids is similar to mt oxidation by generates NO ATP.
What is α-oxidation?
Oxidation of BRANCHED-chain fatty acids from PLANTS occurs with release of terminal carboxyl as CO2.
Problem with carnitine deficiency or carnitine acyltransferase deficiency?
Impairs the use of LONG-CHAIN fatty acids by means of the carnitine shuttle for energy production.
Carnitine or carnitine acyltransferase deficiency - Clinical findings:
1. Muscle aches.
2. Fatigue following exercise.
3. Elevated FFAs in the blood.
4. Reduced ketone production in the liver during fasting (NON ketotic hypoglycemia) --> Acetyl CoA from beta-oxidation is necessary for ketone production.
--> HYPOGLYCEMIA occurs because all tissues are competing for glucose for energy.
Deficiency of medium-chain acyl CoA dehydrogenase (MCAD), the 1st enzyme in the oxidation sequence, is an AR disorder - Clinical findings:
1. Recurring episodes of hypoglycemia (all tissues compete for glucose)
4. Minimal ketone production in the liver.
Main problem in MCAD:
Inability to FULLY metabolize long-chain fatty acids.
XR disorder associated with defective peroxisomal oxidation of very-long fatty acids.
Clinical findings of adrenoleukodystrophy:
1. Adrenocortical insufficiency.
2. Diffuse abnormalities in the cerebral white matter --> Neurologic problems, progressive mental deterioration and spastic paralysis.
Refsum's disease is an ...?
AR disease that is marked by an inability to degrade PHYTANIC acid (α-oxidation deficiency), a plant-derived branched-chain fatty acid that is present in dairy products.
Refsum's disease - Clinical findings:
1. Retinitis pigmentosa.
2. Dry, scaly skin.
3. Chronic polyneuritis.
4. Cerebellar ataxia.
5. Elevated protein in CSF.
Jamaican vomiting sickness is caused by ...?
Eating unripe fruit of the akee tree that contains a toxin - HYPOGLYCIN.
Mechanism of action of hypoglycin:
Inhibition of medium- and short-chain acyl CoA dehydrogenase --> Non ketotic hypoglycemia.