--- module: 089-01 language: en chapter: 89 title: "Lipid Metabolism, Membranes, Lipoproteins, and Ketone Biology" module_title: "Lipid digestion, fatty-acid transport, mobilisation, and beta oxidation" source_sha256: e88649afe4962d18fb428bbce0104f7cfacfad73f272c2c3fd797d34e0c597f8 --- # Lipid digestion, transport, and beta oxidation ## Why lipids need special handling ### Energy, membranes, signals, steroid precursors ### Hydrophobicity demands special transport ### Blocked mobilisation or entry causes energy crisis ## Digestion and absorption ### Dietary lipid is mainly triacylglycerol ### Lingual and gastric lipases: infants, pancreatic failure ### Bile salts emulsify fat into droplets #### Amphipathic, made from cholesterol #### Recycled via terminal ileum and portal blood ### Pancreatic lipase with colipase #### 2-monoacylglycerol and free fatty acids ### Phospholipase A2 and cholesterol esterase ### Mixed micelles cross unstirred water layer ## Packaging and export ### Re-esterification in endoplasmic reticulum ### Transfer protein loads apolipoprotein B-48 #### Chylomicrons exit via lacteals and thoracic duct #### Initially bypass the liver ### Short and medium chains enter portal blood ### Failure causes fat malabsorption #### Fat-soluble-vitamin deficiency ## Delivery and mobilisation ### Lipoprotein lipase on capillary endothelium #### Insulin favours adipose activity after meals #### Remnants cleared by liver receptors ### Adipose lipolysis in fasting and exercise #### Catecholamines and low insulin activate lipases #### Insulin suppresses, promotes re-esterification ### Glycerol goes to liver #### Adipose has little glycerol kinase ### Plasma fatty acids reflect flux, not stores #### Excess: liver fat, insulin resistance #### Albumin binding is finite ## Activation and mitochondrial entry ### Acyl-CoA synthetase costs two phosphate bonds #### Traps fatty acid for its fate ### Carnitine carries acyl groups across inner membrane #### CPT1 on outer membrane #### Translocase swaps acylcarnitine for carnitine #### CPT2 regenerates acyl-CoA in matrix ### Malonyl-CoA inhibits CPT1 #### Fed: carboxylase makes malonyl-CoA #### Fasting: AMP kinase lowers malonyl-CoA ## Beta oxidation and yield ### Four steps remove two carbons per cycle #### FAD dehydrogenation to flavoprotein #### Hydration, then NADH dehydrogenation #### Thiolysis releases acetyl-CoA ### Palmitate: seven cycles, eight acetyl-CoA #### About 106 ATP after activation ### More oxygen per ATP than carbohydrate #### Carbohydrate favoured when oxygen limits ### Red cells lack mitochondria ### Brain uses glucose or ketones ## Special fatty acids ### Unsaturated need isomerase, sometimes reductase ### Odd chains end as propionyl-CoA #### Biotin carboxylase, B12 mutase #### Succinyl-CoA gives limited glucogenic carbon #### Defects: organic acidosis, hyperammonaemia ### Very-long chains start in peroxisomes #### Electrons to oxygen make hydrogen peroxide ### Phytanic acid needs alpha oxidation #### Defects hit retina, nerves, cerebellum ### Omega oxidation yields urinary dicarboxylic acids ## Oxidation disorders ### MCAD deficiency: hypoketotic hypoglycaemia #### Newborn screening allows fasting avoidance ### Primary carnitine deficiency #### Cardiomyopathy, weakness, hypoglycaemia ### Carnitine not universally safe or effective ### Oxidation fuels hepatic gluconeogenesis #### Acetyl-CoA activates pyruvate carboxylase #### Failure: hypoglycaemia with low ketones ## Exercise and integrated control ### Moderate prolonged work burns more fat ### Intense work relies on carbohydrate ### Training raises mitochondria and fat oxidation #### Preserves glycogen ### Intramuscular lipid not itself pathological #### Toxicity from diacylglycerols, ceramides ### Any blocked boundary mimics fuel scarcity #### Diagnose with timing, ketones, acylcarnitines