Flashcards in Lipid Mobilization and Catabolism; Ketone body synthesis and utlization Deck (104):
Fatty acids in TAG are released as free fatty acids during fasting by which enzyme?
Hormone Sensitive Lipase
What inhibits hormone sensitive lipase during the well fed state?
Deficiency of what hormone during fasting stimulates hormone sensitive lipase?
Besides absence of insulin, what else stimulates hormone sensitive lipase?
How does epinephrine stimulate hormone sensitive lipase?
-activates protein kinase
Is hormone sensitive lipase active in the phosphorylated or dephosphorylated form?
Why can't glycerol formed in the adipose tissue from lipolysis be reused?
Adipose lacks glycerokinase
Once glycerol is formed via Lipolysis in adipose tissue, where does it go? What does it do there?
How is free fatty acids transported in circulation?
Once free fatty acids are made via lypolysis, where is it transported to?
Liver and muscle (skeletal; cardiac)
Are free fatty acids oxidized for energy by the brain?
(NOT an important fuel source in brain even in starvation)
In B-oxidation, what part of the fatty acid is oxidized?
B-carbon atom of fatty acid
Where in the cell does B-oxidation occur?
What are the 3 staged of B-oxidation?
-Activation of fatty acid (cytosol)
-Transport of fatty acid into mitochondria
What activates fatty acids to fatty acyl coA in order to initial B-oxidation?
Fatty Acyl CoA synthetase
What is another name for fatty acyl coA synthetase?
What else does thiokinase need along with a fatty acid molecule in order to make fatty acyl coA?
Where is fatty acyl CoA synthetase found?
Outer mitochondrial membrane (cytosolic side)
What is the role of Carnitine Palmitoyl Transferase I (CPT-1)?
Binds Carnitine to the fatty acyl group to form Acyl-Carnitine
How does Acyl-Carnitine cross the inner mitochondrial membrane to enter the mitochondrial matrix?
What is the role of Carnitine Palmitoyl Transferase -II (CPT-II)?
Removes carnitine from acyl group forming Fatty Acyl CoA in the matrx
How does carnitine get from the mitochondrial matrix back to the intermembrane space?
Can fatty acid synthesis occur during the same time as B-oxidation?
How is CPT-I inhibited?
How do fatty acids cross the mitochondrial membrane without the aid of carnitine or CPT?
When they are shorter than 12 C atoms
What tissues are different isoforms of CPT-I and CPT-II located?
Where is the location of the enzymes needed for B-oxidation?
What is the sequence of reactions of B-oxidation?
-Oxidation (removal of H) (req FAD)
-Addition of water
-Oxidation (removal of H) (req NAD+)
One sequence of reactions in B-oxidation results in what?
-Cleavage of 2 C-atoms
(removed as Acetyl CoA)
What enzyme family performs the 1st oxidation step in B-oxidation?
Acyl CoA Dehydrogenase
What enzyme adds water in the second step of B-oxidation?
Enoyl CoA Hydratase
Which enzyme is needed in the 3rd step of oxidation in B-oxidation?
3-hydroxy acyl CoA dehydrogenase (req NAD+)
What performs the cleavage step during B-oxidation?
What energy molecule does Acyl CoA Dehydrogenase create?
FADH2 (equivalent to 2 ATP)
What energy molecule does 3-hydroxy acyl CoA dehydrogenase create?
NADH + H+
What is the most common inherited autosomal recessive enzyme deficiency for B-oxidation
Medium Chain Acyl CoA dehydrogenase (MCAD) deficiency
What can patients with MCAD deficiency not do?
Decreased ability to oxidize fatty acids with 6-10 C atoms
What occurs in patients with MCAD deficiency during fasting?
Why does MCAD deficiency produce severe hypoglycemia?
During fasting, no B-oxidation for energy, therefore rely on glucose.
For patients with MCAD deficiency, what is found in the urine?
-Medium Chain Acyl Carnitines
Why are dicarboxylic acids found in the urine for patients with MCAD deficiency?
Increased flux through omega-oxidation.
In patients with MCAD deficiency, what does the presence of CK-MM and myoglobin in the urine indicate?
Skeletal muscle damage
What are the biochemical consequences of decreased B-oxidation due to MCAD deficiency?
-Dec B-oxidation of MCFAs
-C8-C10 acyl carnitines in blood
-Increased flux through w-oxidation (dicarboxylic acids in urine)
What are the biochemical consequences of hypoglycemia due to MCAD deficiency?
-Dec utilization of fatty acids by peripheral tissues
-Inc reliance on glucose as energy source
-Dec ATP and acetyl CoA to activate gluconeogensis
How does hypoglycemia due to MCAD deficiency effect gluconeogenesis?
Dec ATP and acetyl CoA to activate gluconeogenesis
What are the biochemical consequences of Hypoketonemia due to MCAD deficiency?
-Dec B-oxidation in liver
-Dec substrate for ketogenesis (acetyl CoA)
What is impaired in primary carnitine deficiency?
Carnitine uptake into tissues
How is MCAD deficiency treated?
-Manage hypoglycemia through IV glucose
-Frequent feeding and high carb, low fat diet.
How is carnitine deficiency treated?
-Cease muscle activity and give glucose
CPT-I deficiency primarily affects which form?
Liver isoform (systemic form)
CPT-II deficiency primarily affects which form?
What is a characterization of CPT-1 deficiency?
-elevated serum carnitine
What is a characterization of CPT-II deficiency?
In CPT-II deficiency, what can often be found deposited in muscle?
Lipid deposits (triglycerides)
What does prolonged exercise result in for patients with CPT-II deficiency?
Myoglobinuria and elevated CK-MM levels in serum
In contrary to systemic carnitine deficiency, myopathic carnitine deficiency is limited to a defect of the __________________found in the skeletal and in the cardiac muscle.
Plasma membrane isoform transporter
Why is there muscle weakness in myopathic carnitine deficiency?
Muscle cells do not synthesize carnitine and are dependent on the uptake of carnitine from the blood which was provided by the liver. With the deficiency of the transporter, these cells lack carnitine and we find muscle weakness. Blood carnitine levels are mostly normal. There is no hypoglycemia or hypoketonemia as the liver is functioning normally.
Compare blood data in patients with systemic carnitine shuttle deficiency to blood data in patients with MCAD deficiency
Patients with systemic carnitine shuttle deficiency or with MCAD deficiency have in common that they show low blood glucose and low ketone bodies during fasting due to reduced B-oxidation in liver mitochondria.
Patients with carnitine shuttle deficiency show elevated blood levels of free fatty acids.
Patients with MCAD deficiency show loss of carnitine in form of medium-chain fatty acyl carnitines that accumulate in blood and are released in urine. Also, they show characteristic dicarboxylic acids formed by microsomal B-oxidation which accumulate in blood and urine
What compound in unripe ackee fruit inhibits MCAD?
In general, what are common features of systemic fatty acid oxidation disorders?
What does the oxidation of odd chain fatty acids produce in the final round of B-oxidation?
Propionyl CoA (3C)
What 2 enzymes are needed to convert Propionyl CoA to Succinyl CoA?
Propionyl CoA carboxylase
Methylmalonyl CoA mutase
During odd chain fatty acid B-oxidation, what is the role of Propionyl CoA Carboxylase?
Propionyl CoA --> Methylmalonyl CoA
What cofactor does Propionyl CoA carboxylase need?
What is the role of Methylmalonyl CoA mutase?
Methylmalonyl CoA---> Succinyl CoA
What cofactor does Methmalonyl CoA mutase need?
After oxidation of odd chain fatty acids, what happens to the succinyl CoA?
Enters TCA cycle
How is B-oxidation primarily regulated?
Serum free fatty acid levels
How are serum free fatty acid levels regulated?
(Low insulin/glucagon (during fasting) activates lypolysis.)
How are Very Long Chain fatty acids (22-26C) initially oxidized?
What is Zellweger syndrome?
Defective peroxisomal biogenesis mainly affecting liver and brain
What is found in circulation in patients with Zellweger syndrome?
Levels of C-26 fatty acids
What is phytanic acid?
A dietary branched chain fatty acid, predominantly found in dairy products
Where does alpha-oxidation of phytanic acid take place?
What is Refsum disease?
disorder characterized by deficiency of peroxisomal phytanyl CoA alpha-hydroxylase (defect in alpha-oxidation)
In Refsum disease, what accumulates?
phytanate accumulates in tissues, esp neurological tissues
How is Refsum manifested?
In disorders where B-oxidation are defective, what alternate pathway is utilized?
What is the major difference between B-oxidation in mitochondria and B-oxidation in peroxisomes?
In contrast to B-oxidation found in mitochondria, FADH2 formed in the first peroxisomal B-oxidation step leads to hydrogen peroxide inside of peroxisomes (instead of eventually joining the ETC via other flavoproteins.)
What is the product of w-oxidation?
In the liver, once acetyl CoA is formed, where does it go?
Either to Krebs cycle
In tissues besides the liver, once acetyl CoA is formed, where does it go?
What are the ketone bodies?
Once acetoacete and 3-hydroxybutyrate are generated, where do they go?
Transported to peripheral tissues where they are reconverted to acetyl coA and then oxidized by TCA cycle
Are ketone bodies soluble in aqueous solutions such as blood?
What is the role of Thiolase in ketogensis?
Takes 2 acetyl CoAs and converts it to Acetoacetyl CoA
What is the role of HMG CoA synthase in ketogenesis?
Catalyzes the 2nd rxn.
-Acetoacetyl CoA ---> HMG CoA
Besides ketogenesis, what else is HMG CoA synthase used for?
Cholesterol synthesis in cytosol.
Where does ketogenesis take place?
In liver mitochondria only
What can acetoacetate be spontaneously decarboxylated to?
Acetone, which is exhaled and can be smelled in the breath of Type I diabetic patients
When does the liver synthesize ketone bodies?
-Fight or flight situations
Acetoacetate is a ketone body. Why is it not possible to release acetoacetate out of acetoacetyl CoA ?
The liver does not contain an enzyme that cleaves mitochondrial acetoacetyl CoA to free acetoacetate and free CoA. Acetoacetyl CoA itself cannot leave mitochondria
Which enzyme is the regulated enzyme of ketone body synthesis?
Mitochondrial HMG CoA synthase is the regulated enzyme of ketone body synthesis
What is the advantage to use acetoacetate and form 3-hydroxybutyrate from it during ketone body synthesis in liver mitochondria?
During ketone body synthesis, the NADH levels in mitochondria are high.
The formation of 3-hydroxybutyrate from acetoacetate in liver mitochondria uses NADH and regenerates NAD+ which can be used for another round of B-oxidation.
Once made, how are ketone bodies utilized?
Utilized in peripheral tissues (skeletal muscle, cardiac muscle, brain)
During the utilization of ketone bodies, what happens to 3-hydroxybutyrate?
Oxidized to acetoacetate
Regarding ketone body utilization, how is acetoacetate activated to acetoacetyl CoA?
Succinyl CoA:acetoacetate CoA transferase (thiophorase)
What is another name for Succinyl CoA:acetoacetate CoA transferase
Regarding ketone body utilization, what happens to Acetoacetyl CoA
Converted to two Acetyl CoA (via Thiolase), which are then used in TCA cycle
Why can't ketone bodies be used by the liver?
Thiophorase is present ONLY in peripheral tissues.
Why does uncontrolled diabetes mellitus cause ketoacidosis?
In uncontrolled diabetes mellitus, lipolysis in adipose tissue is excessive and uncontrolled (due to low levels of circulating insulin)
In uncontrolled diabetes mellitus, how is the production of ketone bodies by the liver compared to the rate of utilization by peripheral tissues.
Production is greater than utlization, resulting in ketonemia
What types of acids are ketone bodies?
Weak acids and tend to lose protons