Lipid Metabolism
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Direct answer
Fatty acid synthesis runs in the cytosol of the fed state, where the biotin enzyme acetyl-CoA carboxylase makes malonyl-CoA and insulin opens the pathway to palmitate; degradation runs inside mitochondria after the carnitine shuttle, whose rate-limiting enzyme carnitine palmitoyl transferase-1 is switched off by malonyl-CoA so that synthesis and oxidation never run together. Each β-oxidation spiral releases 1 FADH2, 1 NADH and one acetyl-CoA, and a full palmitate yields about 106 ATP by modern counting (129 by the older convention). In fasting, the liver converts surplus acetyl-CoA into the ketone bodies acetoacetate, β-hydroxybutyrate and acetone; the brain consumes them after about three days of starvation, but the liver itself never can, lacking thiophorase.
What you must remember
- Fatty acid synthesis is cytosolic, NADPH-dependent (pentose phosphate pathway) and ends at palmitate; citrate carries acetyl units out of mitochondria and activates acetyl-CoA carboxylase.
- Carnitine palmitoyl transferase-1 on the outer mitochondrial membrane is the rate-limiting step of β-oxidation; medium-chain fatty acids skip the carnitine shuttle entirely, the basis of medium-chain triglyceride use in malabsorption.
- Ketogenesis is gated by mitochondrial HMG-CoA synthase in the liver; ketolysis needs thiophorase, present in muscle, heart, kidney and the adapted brain but absent in liver — the liver makes ketones but cannot eat them.
- The urine nitroprusside strip detects acetoacetate, not β-hydroxybutyrate; in diabetic ketoacidosis β-hydroxybutyrate predominates, so the strip can understate severity and paradoxically darken as the patient recovers and β-hydroxybutyrate converts back to acetoacetate.
- Medium-chain acyl-CoA dehydrogenase deficiency is the commonest inborn error of fatty acid oxidation: fasting-induced hypoketotic hypoglycaemia with dicarboxylic aciduria in infancy; management is frequent feeding and carbohydrate, never fasting.
- Lipoprotein anchors: chylomicrons carry dietary fat with apoB-48, and apoC-II activates lipoprotein lipase at capillary endothelium; VLDL (apoB-100) carries hepatic triglyceride; LDL delivers cholesterol via the LDL receptor; HDL with apoA-I and LCAT runs reverse transport.
- Lipoprotein lipase deficiency (type I hyperlipoproteinaemia) gives eruptive xanthomas, recurrent abdominal pain from pancreatitis and creamy plasma in a child; familial hypercholesterolaemia is the type II counterpart with tendon xanthomas.
- Linoleic and α-linolenic acids are essential; arachidonic acid derives from linoleic acid and feeds the prostaglandin and leukotriene cascades.
- Hormone-sensitive lipase in adipose tissue is activated by catecholamines through cAMP and switched off by insulin.
A worked case: the toddler who vomited after skipping dinner
A two-year-old skips dinner during a viral illness and is found drowsy the next morning; glucose is 34 mg/dL and the urine ketone strip is only faintly positive. The combination is the clue: hypoglycaemia should drive ketogenesis hard, so hypoketotic hypoglycaemia means the machinery for making ketones is broken. Walk the chain: fasting → hormone-sensitive lipase releases free fatty acids → hepatic β-oxidation should generate acetyl-CoA and then ketones; in medium-chain acyl-CoA dehydrogenase deficiency the spiral stalls at C8–C10, acetyl-CoA never accumulates, and the omega-oxidation route dumps dicarboxylic acids into the urine instead. Contrast the diabetic child in ketoacidosis, whose glucose and ketones are both high because insulin absence and glucagon excess maximise both lipolysis and ketogenesis. Immediate management is dextrose; long-term management is avoiding fasting, using uncooked cornstarch at night if needed, and carnitine supplementation where secondary depletion is documented. Newborn screening now catches most cases by the octanoylcarnitine (C8) peak on tandem mass spectrometry before the first crisis.
Where students slip
The nitroprusside strip's blind spot for β-hydroxybutyrate is the single most tested trap; the strip paradoxically darkens during recovery as β-hydroxybutyrate converts back to acetoacetate. Second, the liver's thiophorase absence is forgotten, so candidates imagine the liver consuming the ketones it makes. Third, carnitine palmitoyl transferase-1 and -2 are swapped: CPT-1 is the regulated outer-membrane enzyme inhibited by malonyl-CoA, while CPT-2 deficiency presents as adolescent exercise-induced rhabdomyolysis with myoglobinuria. Fourth, chylomicron versus VLDL is judged without asking whether the sample was fasting — post-prandial turbidity is chylomicron (type I) until proved otherwise, fasting turbidity VLDL (type IV). Fifth, ketosis of starvation is physiological; ketoacidosis needs insulin deficiency plus glucagon excess.
Frequently asked questions
Why cannot the liver utilise the ketone bodies it produces?
It lacks thiophorase (succinyl-CoA:3-ketoacid CoA transferase), so ketolysis is reserved for extrahepatic tissues such as muscle, heart, kidney and the adapted brain.
Which ketone body is highest in diabetic ketoacidosis, and what does the strip detect?
β-hydroxybutyrate predominates; the nitroprusside strip detects acetoacetate only, understating severity at presentation.
Which enzymes are rate-limiting for fatty acid synthesis and oxidation?
Acetyl-CoA carboxylase for synthesis and carnitine palmitoyl transferase-1 for oxidation — with malonyl-CoA simultaneously driving the former and blocking the latter.
Which apolipoprotein activates lipoprotein lipase?
ApoC-II, transferred to chylomicrons and VLDL from HDL; its defect causes type I hyperlipoproteinaemia with eruptive xanthomas.
Which fatty acids are dietary essentials, and why?
Linoleic (ω-6) and α-linolenic (ω-3) acids; humans lack the desaturases to insert double bonds beyond carbon 9, and arachidonic acid comes from linoleate.
What is the classic presentation of medium-chain acyl-CoA dehydrogenase deficiency?
Fasting-induced hypoketotic hypoglycaemia with vomiting and lethargy in infancy, dicarboxylic aciduria, and a C8 acylcarnitine peak on newborn screening.