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)
