Adipose Tissue Lipolysis; Fatty Acid Oxidation Flashcards
Summarize lipid mobilization from adipose tissue
- Triacylglycerol (TAG) is storage form of lipid
- Lipid droplets in white adipose tissue
- Fatty acids in TAG released as free fatty acids (non- esterified fatty acids) by HS Lipase
• Hormone sensitive (HS) lipase
– Inhibited by insulin (inactive on dephosphorylation)
– Low levels of insulin (fasting), stimulates HS lipase
– Epinephrine stimulates HS lipase (Phosphorylated active)
What is the role of epinephrine?
Role of Epinephrine: Fasting, flight and fight
• Activates protein kinase A
• Phosphorylation of HS Lipase - facilitates
binding to lipid droplet
• Stimulates hydrolysis of TAG to free fatty acids and glycerol
What is the fate of glycerol?
- Glycerol formed by adipose tissue lipolysis, cannot be reused in adipose tissue, as adipocytes lack glycerokinase
- Glycerol goes to liver, where it enters glycolysis or gluconeogenesis or triacylglycerol synthesis
Give an overview of fatty acid oxodation
- Free fatty acids bound to albumin in circulation
- Free fatty acids transported to liver and muscle (skeletal and cardiac muscle) – major sites of -oxidation
- Free fatty acids NOT oxidized by brain; Fatty acids NOT important fuel for brain even during prolonged starvation
- Fatty acids cannot be oxidized by cells that lack mitochondria (RBCs) or oxygen
What is B-oxidation?
- Oxidation of fatty acids at β-carbon atom of fatty acid
- Intracellular location: Mitochondria
• Stages of β-oxidation
– Activation of fatty acid (cytosol)
– Transport of fatty acid from cytosol to mitochondria
– β-oxidation proper (reactions of β-oxidation)
How are fatty acids activated?
Activated to fatty acyl CoA by Fatty acyl CoA synthetase (thiokinase)
• Present in outer mitochondrial membrane (cytosolic side)
Describe the transport of fatty acid from cytosol to mitochondria
- CPT-I. and CPT-II inouter and inner mitochondrial membrane-respectively
- CPT-I and CPT-II isoforms in liver and muscle
- Fatty Acyl CoA cannot travel through inner mitochondrial membrane
- Carnitine binds acyl group to form acyl-carnitine (CPT-I)
- Acyl carnitine transported across inner mitochondrial membrane via translocase
- Acyl CoA formed in matrix (CPT-II) and used for β-oxidation
- Carnitine transported back to intermembrane space via translocase
- Regulation: Malonyl CoA inhibits CPT-I (when fatty acid synthesis is active, - oxidation inhibited)
- Note: Fatty acids shorter than 12 C atoms cross mitochondrial membrane without carnitine or CPT
What are the reactions of B-oxidation?
Enzymes in mitochondrial matrix
• Sequence of reactions of β-oxidation
– Oxidation (removal of H) (requires FAD)
– Addition of water
– Oxidation (removal of H) (requires NAD+)
– Cleavage
- One cycle of -oxidation: sequence of four reactions
- Results in cleavage of 2 C-atoms (removed as acetyl CoA)
What is the energy yield of B oxidation of palmitic acid?
- B-oxidation of 16C palmitic acid = 8 Acetyl CoA, 7FADH2, 7NADH+H+
- 8 Acetyl CoA x 12 ATP (Krebs cycle) = 96 ATP
- 7FADH2 x 2 ATP = 14 ATP
- 7NADH+H+ x 3 ATP = 21 ATP
- Total = 131 ATP
- -2 ATP for activation of fatty acid (Fatty acyl CoA synthetase)
- Net ATP formed = 129 ATP (Also refer Fig 16.18 – Lippincott’s)
- Compare to oxidation of glucose (38 ATP per mole of glucose)
- (1NADH=2.5ATP and 1FADH2=1.5ATP; We use 1NADH =3ATP and 1FADH2=2ATP for ease of calculation)
Summarize fatty acid oxidation in liver
• Overnight fast, 60-70% energy from fatty acid oxidation
• Beta-oxidation in liver is important for
– Gluconeogenesis: Energy and acetyl CoA (activator of pyruvate
carboxylase)
– Ketone body synthesis: Acetyl CoA for ketogenesis
• Systemic fatty acid oxidation disorders (MCAD deficiency,
carnitine deficiency, CPT-I deficiency): Affects liver
– Hypoglycemia (Cells rely on glucose for energy and reduced
gluconeogenesis) – Acetyl CoA absolute activator for pyruvate
carboxylase (gluconeogenesis)
– Hypoketosis (reduced formation of acetyl CoA)
Describe fatty acid oxodation in skeletal muscle
Skeletal muscle uses fatty acid oxidation during low-intensity prolonged
activity (Endurance or Aerobic)
- Provide energy for Aerobic Exercise
- Myopathic fatty acid oxidation disorders: Defect in fatty acid oxidation restricted to muscles (Skeletal and cardiac)
– Manifests as Cramps during low-intensity, sustained, aerobic activity (compare to muscle glycogen storage disorder)
– Unable to perform aerobic exercise
What are the lab findings in Myopathuc fatty acid oxidation disorders?
Lab findings:
– Blood lactate levels rise following ischemic exercise (Indicates normal anaerobic metabolism)
– Myoglobinuria, and elevated levels of serum CK-MM;
– Muscle biopsy shows: Lipid droplets in muscle
What are the systemic fatty acid oxidation disorders?
- Systemic fatty acid oxidation disorders
- Organs affected: Liver and muscle
• Hypoglycemia and hypoketosis
(metabolic crisis) following an illness
• Seen in: MCAD deficiency/ CPT-I
deficiency/ systemic carnitine deficiency
What are the myopathic fatty acid oxidation disorders?
• Myopathic fatty acid oxidation disorders
- Organs affected: Muscle (Skeletal and cardiac)
- Muscle cramps during aerobic exercise
• Lab tests: Myoglobinuria and increased
CK-MM levels
• Muscle biopsy: Elevated muscle
triacylglyerol (Lipid droplets in muscle)
• Seen in: Myopathic carnitine deficiency/ CPT-II deficiency
What are the signs and symptoms of MCAD defociency?
Autosomal recessive disorder
• Age of presentation: 6 -24 months
• Severe hypoglycemia (metabolic crisis) on fasting or illness
– Tissues (liver, muscle) cannot utilize fatty acids for energy. Glucose is sole
source of energy, results in profound hypoglycemia – Impaired gluconeogenesis: Less ATP and acetyl CoA
• Decreased oxidation of medium chain fatty acids (6 -10 C atoms) • Medium chain acyl carnitines (6-10 C) in urine: Typical lab finding • Dicarboxylic acids in urine (Increased ω-oxidation)
What are the consequences of MCAD deficiency?
B-oxidation
- Decreased β oxidation of medium chain fatty acids
- C8-C10 acyl carnitines in blood and urine
- Increased ω-oxidation (Dicarboxylic acids in urine)
Hypoglycemia
- Decreased oxidation of fatty acids by peripheral tissues
- Increased reliance on glucose for energy
- Decreased ATP and acetyl CoA to activate gluconeogenesis
Hypoketonemia
- Decreased β-oxidation in liver
- Decreased substrate for ketogenesis (acetyl CoA)
Describe cartinine deficiency
• Impaired Carnitine uptake into tissues (Refer Pg 191 in textbook)
• Transport of long chain fatty acids into mitochondria is impaired,
and -oxidation is decreased
• Systemic carnitine deficiency: Early age of presentation
• Hypoglycemia due to impaired gluconeogenesis (Acetyl CoA)
• Hypoketosis
• Myopathic carnitine deficiency: Muscle weakness and
cardiomyopathy (Later age of presentation)
- Unable to tolerate aerobic activity (Cramps during aerobic exercise)
- Elevated serum CK-MM and myoglobin in urine: Skeletal muscle damage
- Lipiddropletsinmusclebiopsy
What are the types of CPT deficienes ?
• CPT-I deficiency: Hypoglycemia and hypoketosis – Affects liver isoform (systemic form)
• CPT-II deficiency: Cardiomyopathy and muscle weakness (myopathic form)
– Unable to tolerate aerobic activity (Cramps during aerobic exercise) – Lipid deposits (triglycerides) in skeletal muscle
– Myoglobinuria and elevated serum CK-MM levels
– Affects muscle isoform
What are the metabolic myopathies?
- Acid maltase deficiency (Pompe)
- Muscle phosphorylase deficiency (McArdle)
- Debrancher enzyme deficiency (Cori disease)
- Phosphofructokinase deficiency (Tarui)
- Phosphoglycerate kinase deficiency
- Phosphoglycerate mutase deficiency
- Lactate dehydrogenase deficiency
- Carnitine palmityl transferase-II deficiency
- Carnitine deficiency
- Myoadenylate deaminase deficiency
Skeletal muscle depends on energy from carbohydrates and fats. Fuels stored in muscle (glycogen) or imported directly from bloodstream (glucose and fatty acids)
How are fatty acid oxidation disirders managed?
• Systemic Fatty acid oxidation disorders -MCAD deficiency/ CPT-I deficiency/ Carnitine deficiency (Manage hypoglycemia)
– Manage hypoglycemia using IV glucose
– Frequent feeding; high carbohydrate, low fat diet. Avoid fasting – Carnitine supplements
• Myopathic fatty acid oxidation disorders
– Myopathic carnitine deficiency/ CPT-II deficiency (symptoms are primarily myopathic)
– Cease muscle activity and give glucose – Carnitine supplements
What is Jamaican vomitting sickness?
- Eating unripe ackee fruit (Caribbean and Africa)
- Results in hypoglycemia and vomiting(2-6hours)
- Contains ‘hypoglycin A’ - inhibitor of MCAD
- Inhibition of β-oxidation leads to profound hypoglycemia (explain why)
- Drowsiness(Hypoglycemia),comaanddeath
- Medium chain acyl carnitines found in urine
Describe the oxidation of odd chain fatty acids
Forms propionyl CoA (3C) in final
round of B-oxidation
- Propionyl CoA → → succinyl CoA (via propionyl CoA carboxylase and methylmalonyl CoA mutase)
- Succinyl CoA enters TCA cycle
How is B-oxidation regulated?
• Serum free fatty acid levels regulate rate of fatty acid
oxidation
– Low insulin/ glucagon ratio (fasting) activates hormone sensitive
lipase in adipose tissue (lipolysis)
– High insulin/glucagon ratio (fed state) inhibits HS lipase
• Entry of fatty acids into mitochondria by CPT-I
– Malonyl CoA (fatty acid synthesis) inhibits CPT-I
– -oxidation and fatty acid synthesis do not occur simultaneously (Reciprocal regulation)
What are the characteristics of Muscle Glycogen storage disorder (McArdle disorder) ?
- Cramps during anaerobic exercise (strenuous exercise)
- NO increase in blood lactate following ischemic exercise
- Muscle biopsy: Excessive Glycogen accumulation
- Elevated serum CK-MM and myoglobinuria
What are the Myopathic fatty acid oxidation defect characteristics?
• Cramps during aerobic exercise
• Blood lactate levels increase following
ischemic/ anaerobic exercise
- Muscle biopsy: Excessive lipid (TAG) droplets
- Elevated serum CK-MM and myoglobinuria
What are the characteristics of hormone sensitiveblipase?
Location: Within adipocytes
- Role of insulin: Insulin inhibits HS lipase
- Action: Breaks down storage TAG in adipose tissue to free fatty acids and glycerol
- Lab marker for increased HS lipase activity: Elevated serum free fatty acids
• Increased HS lipase activity seen in – Starvation
– Insulin resistance (Metabolic syndrome)
– Uncontrolled type 1 diabetes mellitus – HS lipase activity markedly increased
What are the characteristics of Lipoprotein lipase?
- Location: Endothelium of blood vessels in adipose tissue and muscle
- Insulin induces lipoprotein lipase and required for optimum activity
- Action: breaks down TAG in lipoproteins (chylomicrons and VLDL) to free fatty acids that enter adipocytes and form TAG for storage within adipocytes
- Lab marker for low lipoprotein lipase activity: Increased TAG; and Increased VLDL
• Decreased activity of lipoprotein lipase is seen in
– Insulin resistance (Metabolic syndrome)
– type 2 diabetes mellitus – this results is increased serum TAG (VLDL) – which in turn increases the risk for cardiovascular disease (macrovascular complications)
What is the purpose of pancreatic lipase?
Enzyme for digestion of dietary TAG
