--- module: 089-03 language: en chapter: 89 title: "Lipid Metabolism, Membranes, Lipoproteins, and Ketone Biology" module_title: "Fasting adaptation, ketone-body metabolism, ketoacidosis, and lipid disorders" source_sha256: c27c2518ed59889d7b6db47416fdc3ffedd7ca55f06e722530a5bf1d69224cbc --- # Fasting, ketones, and lipid disorders ## Hormonal direction of fuel ### Insulin promotes storage, suppresses release #### Blocks lipolysis, ketogenesis, proteolysis ### Glucagon supports hepatic glucose output ### Insulin-to-glucagon ratio sets direction ## Stages of fasting ### Overnight: liver glycogen maintains glucose ### Lipolysis releases fatty acids and glycerol #### Muscle and liver oxidise fat, sparing glucose ### Glycerol, lactate, alanine feed gluconeogenesis ### After about a day gluconeogenesis dominates #### Powered by fatty-acid oxidation ### Ketones reduce brain glucose use #### Spares muscle protein ## Ketogenesis ### Hepatic mitochondrial matrix ### Acetyl-CoA exceeds cycle capacity #### Oxaloacetate diverted to gluconeogenesis #### High NADH slows the cycle ### HMG-CoA synthase then lyase ### Acetoacetate reduced to beta-hydroxybutyrate #### Set by NADH-to-NAD ratio ### Acetone forms spontaneously, exhaled ## Ketone use ### Liver lacks thiophorase ### Extrahepatic tissues activate acetoacetate #### Split to two acetyl units and oxidised ### Heart, muscle, renal cortex, adapted brain ### Red cells cannot use ketones ### Brain still needs some glucose #### Glycerol and glucogenic amino acids supply it ## Ketosis versus ketoacidosis ### Nutritional ketosis keeps restraining insulin #### pH regulated, kidneys excrete acid ### Concentration alone does not define acidosis ### Diabetic ketoacidosis: severe insulin deficiency #### Malonyl-CoA falls, entry accelerates #### Osmotic diuresis amplifies disorder ### High-anion-gap metabolic acidosis #### Kussmaul breathing compensates ### Potassium depleted despite normal serum level ## Treating ketoacidosis ### Fluids, insulin, measured potassium, precipitant ### Add glucose so insulin can continue ### Bicarbonate rarely needed ### SGLT2 inhibitors: only modest hyperglycaemia ### Alcoholic ketoacidosis #### High NADH favours beta-hydroxybutyrate #### Thiamine, dextrose, electrolytes ### Nitroprusside mainly detects acetoacetate #### Underestimates severity, high in recovery ## Ketone signalling and starvation ### Beta-hydroxybutyrate is also a signal #### Universal benefit claims exceed evidence ### Ketogenic diet reduces some seizures ### Prolonged fasting lowers energy expenditure ### Refeeding shifts phosphate, potassium, magnesium #### Thiamine, cautious start, monitoring ## Lipid disorders ### Steatosis: supply exceeds oxidation and export #### Hepatic lipogenesis stays insulin responsive ### Very high triglycerides cause pancreatitis ### Familial hypercholesterolaemia #### Tendon xanthomas, premature vascular disease ### Acid lipase deficiency and Niemann-Pick C ### Sphingolipids accumulate in macrophages or neurons #### Enzyme replacement rarely reaches the brain ### Adrenoleukodystrophy: very-long-chain transport ### Zellweger spectrum: peroxisome assembly ## Adipose tissue and integration ### Obesity: adipose expansion and dysfunction #### Ectopic lipid drives insulin resistance ### Brown fat makes heat via uncoupling protein 1 #### Appetite offsets pharmacological activation ### Fasting is an interorgan negotiation #### Lost insulin and renal restraint: danger