Adipose Lipolysis, Fatty Acid Oxidation and Ketogenesis

Question 1

describe the purpose of hormone sensitive lipase

Answer 1

• releases fatty acids in the TAG as free fatty acids (non-esterified FAs)
• HS lipase is inhibited by insulin in the well fed state
  
  • inactive in the dephosphorylated state

Question 2

which tissues utilize free fatty acids?

Answer 2

• free fatty acids are transported to liver and muscle (skeletal and cardiac) which are major sites of B-oxidation
• free fatty acids ARE NOT oxidized for energy by the brain
  
  • fatty acids are not an important fuel source for the brain even during prolonged starvation

Question 3

what is the fate of glycerol?

Answer 3

• glycerol formed in the adipose tissue cannot be reused in the adipose tissue as the adipose tissue lacks glycerokinase
• glycerol goes to the liver where it enters glycolysis or gluconeogenesis or TAG synthesis

Question 4

describe location and stages of B-oxidation

Answer 4

• oxidation of FAs at the B-carbon atom of the FA
• occurs in the mitochondria
• stages:
  
  • activation of the FA (cytosol)
  • transport of FA from the cytosol to mt
  • B-oxidation proper (reactions of B-oxidation)

Question 5

describe the activation of fatty acid

Answer 5

Question 6

describe the transport of fatty acid from cytosol to mt

Answer 6

Question 7

describe the transport of fatty acid from the cytosol to mt

Answer 7

• CPT-1 and CPT-II are present in the outer and inner mt membrane
  
  • different isoforms in liver and muscle
• acyl CoA cannot traverse through the inner mt membrane
• carnitine binds to the acyl group to form acyl-carnitine (CPT-I)
• acyl carnitine is transported across the inner mt membrane via translocase
• acyl CoA is formed in the matrix (CPT-II) and is used for B-oxidation

Question 8

complete B-oxidation of 16C palmitic acid results in the formation of ______

Answer 8

• 8 acetyl CoA (16/2)
• 7 FADH2 (7 rounds of B-oxidation)
• 7 NADH (7 rounds)

Question 9

describe the sequence of fatty acid breakdown

Answer 9

LCAD/MCAD/SCAD = long/medium/short chain acyl CoA dehydrogenase

Question 10

what cofactor does acyl CoA dehydrogenase require?

Answer 10

FAD

Question 11

describe MCAD deficiency

Answer 11

• most common inheritied autosomal recessive enzyme def.
• characterized by a decreased ability to oxidize fatty acids with 6-10 C atoms (medium chain fatty acids)
• manifested by severe hypoglycemia
  
  • during fasting, the tissues (liver + muscle) are not able to utilize FAs as an energy source; the tissues rely on glucose for their source of energy, resulting in the profound hypoglycemia
• long chain FAs are oxidized to medium chain acyl CoA (8-10C)
• medium chain acyl carnitines are excreted in the urine
• dicarboxylic acids are found in urine (due to increased flux through ω-oxidation)

Question 12

name the biochemical consequences of MCAD deficiency

Answer 12

Question 13

describe carnitine deficiency

Answer 13

• carnitine uptake into tissues is impaired
• transport of long chain fatty acids into the mt is impaired and B-oxidation is reduced
• systemic carinitine deficiency: presents at early age
  
  • hypoglycemia due to impaired B-oxidation and impaired gluconeogenesis (needs acetyl CoA as activator)
• myopathic carnitine deficiency: presents at later age
  
  • ​ is characterized by muscle weakness and cardiomyopathy
  • presence of CK-MM and myoglobin in urine indicates skeletal muscle damage
  • lipid droplets in muscle biopsy

Question 14

describe CPT-I and CPT-II deficiency

Answer 14

• CPT-I deficiency is characterized by a hypoglycemia and hypoketosis and commonly affects the liver isoform (systemic form)
• CPT-II deficiency is characterized by cardiomyopathy and muscle weakness (myopathic form).
  
  • Lipid deposits (triglycerides) are found in skeletal muscle
  • prolonged exercise results in myoglobinuria and elevated CK-MM levels in serum
  • CPT-II deficiency commonly affects the muscle

Question 15

describe Jamaican vomiting sickness

Answer 15

• ingestion of the unripe ackee fruit results in hypoglycemia and vomiting
• fruit contains hypoglycin A that is an inhibitor of MCAD
• medium chain acyl carnitines are found in urine

Question 16

describe the oxidation of odd chain FAs

Answer 16

succinyl CoA can then enter the TCA cycle

Question 17

describe peroxisomal oxidation of fatty acids

Answer 17

• very long chain fatty acids (22 to 26 C) are initially oxidized in the peroxisomes; the shortened fatty acid next transported to the mt for further oxidation
• Zellweger syndrome is characterized by defective peroxisomal biogenesis mainly affecting the liver and brain
  
  • levels of 26-C FAs in circulation are increased in Zellweger syndrome
• neurological manifestations (delayed development) and extensive demyelination are seen
• hepatomegaly and hepatocellular failure

Question 18

describe α-oxdiation of branched chain fatty acids and the associated disorder

Answer 18

• phytanic acid is a dietary branched chain fatty acid, predominant in dairy products
• α-oxidation of phytanic acid takes place in peroxisomes
• Refsum disease is a disorder characterized by deficiency of the peroxisomal phytanyl CoA α-hydroxylase (defect in α-oxidation)
  
  • phytanate accumulates in tissues (neurological tissue)
  • management includes dietary restriction of branched chain FAs

Question 19

describe ω-oxidation

Answer 19

• minor pathway for oxidation of FAs in the ER
• ω-oxidation results in the oxidation of the ω-C of the FA forming a dicarboxylic acid
• in disorders where B-oxidation is defective (MCAD deficiency), dicarboxylic acids may be found in circulation and in urine

Question 20

describe the further fate of acetyl CoA

Answer 20

Question 21

describe ketone bodies

Answer 21

• acetyl CoA from fatty acid oxidation are converted to ketone bodies in liver (peripheral tissues cannot synthesize ketone bodies)
• the ketone bodies are acetoacetate, 3-hydroxybutyrate (B-hydroxybutyrate) and acetone
• acetoacetate and 3-hydroxy butyrate are transported to peripheral tissues
  
  • in peripheral tissues, they are reconverted to acetyl CoA that are oxidized by TCA cycle

Question 22

describe the steps of ketogenesis

Answer 22

Question 23

explain when 3-hydroxybutyrate is normally formed

Answer 23

• 3-hydroxybutyrate is formed from acetoacetate when the ratio of NADH/NAD is increased (as occurs when B-oxidation is predominant)
• during fasting (ketoacidosis), the major ketone body is 3-hydroxybutyrate

Question 24

describe the utilization of ketone bodies

Answer 24

• ketone bodies are formed in liver and utilized in peripheral tissues (skeletal, cardiac, brain)
• ketone bodies provide an alternate fuel source for the brain in prolonged fasting
• 3-hydroxybutyrate is oxidized to acetoacetate
  
  • acetoacetate is activated toa cetoacetyl CoA by succinyl CoA:acetoacetate CoA transferase (thiophorase)
    
    • this is only in the peripheral tissues, not the liver, so the liver cannot use the ketone bodies

Question 25

describe the flowchart of utilization of ketone bodies

Answer 25

Question 26

describe the changes in levels of metabolites in fasting

Answer 26

Question 27

explain why there is increased ketogenesis during starvation

Answer 27

Question 28

describe the relationship between B-oxidation and gluconeogenesis

Answer 28

• B-oxidation provides energy and acetyl CoA to activate gluconeogenesis, BUT the C atoms of acetyl CoA (FAs) are NOT directly used as precursors of gluconeogenesis
  
  • C atoms are derived from glutamine, alanine, lactate, glycerol

Question 29

explain why ketoacidosis is uncontrolled in type I diabetes mellitus

Answer 29

• in uncontrolled diabetes mellitus, lipolysis in adipose tissue is excessive and uncontrolled (due to very low levels of circulating insulin), which means hormone sensitive lipase is very active
• the production of ketone bodies by the liver is greater than the rate of ketone body utilization by the peripheral tissues, resulting in very high levels of ketone bodies in circulation (ketonemia)
• ketone bodies are excreted in urine (ketonuria) – detected by dipstick methods
• ketone bodies are weak acids and tend to lose H+; these H+ are buffered by HCO3, thus the serum HCO3 levels fall, resulting in severe acidosis

Question 30

which metabolites are high during ketoacidosis in uncontrolled type I diabetes mellitus?

Answer 30

• 3-hydroxybutyrate and acetoacetate levels in the blood and urine are very high
• acetone production is also increased
  
  • fruity odor of breath is due to loss of acetone (volatile)