Expansion
Hormone sensitive lipase releases it, albumin carries it, carnitine admits it
Expansion
Three steps from adipocyte to mitochondrion
- Mobilisation: hormone sensitive lipase hydrolyses stored triglyceride, releasing free fatty acids and glycerol. Activated by glucagon, adrenaline and cortisol, inhibited by insulin
- Transport: free fatty acids travel bound to albumin; glycerol goes to the liver for gluconeogenesis
- Entry: long chain fatty acids need the carnitine shuttle (CPT1, translocase, CPT2) to cross the inner mitochondrial membrane. Short and medium chain fatty acids enter freely
“Only long chains need the ferry.”
CPT1 is the rate limiting step, and it is inhibited by malonyl-CoA, the first committed intermediate of fatty acid synthesis. This is elegant reciprocal regulation: when the cell is making fat it cannot simultaneously burn it.
Beta oxidation then removes two carbons per cycle, yielding 1 FADH2, 1 NADH and 1 acetyl-CoA each time.
Clinical correlates
- MCAD deficiency is the commonest fatty acid oxidation defect, on the newborn screen. It causes hypoketotic hypoglycaemia during fasting or illness, because fat cannot be used and ketones cannot be made. Management is avoidance of fasting
- Carnitine deficiency, primary or secondary to valproate or dialysis, causes muscle weakness, cardiomyopathy and hypoketotic hypoglycaemia
- Fatty acids cannot be converted to glucose in humans, because acetyl-CoA cannot cross back to pyruvate, which is why prolonged starvation still requires protein breakdown