MBC - Cell Metabolism 2 Flashcards
Five main lipid classes
Free fatty acids, triacylglycerols, phospholipids, glycolipids, steroids; hydrocarbon chain with terminal carboxylic acid group, saturated = no double bonds, often stored as triacylglycerols in cells’ cytoplasm (3 fatty acids + 1 glycerol attached by ester linkages which help neutralise carboxylic acid groups and keep pH in cells within normal range, reduced and anhydrous = good storage molecule
Fat transportation - Metabolism
Acetyl CoA production, most cellular oxidation reactions + ATP (cellular), beta oxidation
Fat transportation - 3 primary sources
Diet, de novo biosynthesis (liver, lipogenesis), adipose storage deposits
Fat transportation - bile salts
Solubilise dietary fatty acids, generated by liver, stored in gallbladder, during digestion pass from bile duct into intestine, emulsify fats aiding their digestion and absorption (also of fat-soluble vitamins A,D,E,K)), lack = majority of fat passing through gut undigested and un absorbed resulting in steatorrhea (fatty stool)
Fat transportation - orlistat
Obesity treatment, inhibitor of gastric and pancreatic lipases, chemically synthesised derivative of lipstatin (product of streptomyces toxytricini), reduces fat absorption by 30% (almost completely excreted by feces), large multi- centre randomised clinical trials -> treating obesity for up to 2 years, side effects -> abdominal pain, dedicating urgency, increased flatus and steatorrhea, aka tetrahydrolipstatin
Fat transportation - lipoproteins (categories)
Categorised according to density: chylomicrons (CM, intestines, dietary fat transport), very low density (VLDL, liver, endogenous fat transport), intermediate density (IDL, VLDL+LDL precursor), low density (LDL, cholesterol transport), high density (HDL, liver, reverse cholesterol transport)
Fat transportation - lipoproteins (chylomicron)
Digested dietary products absorbed by enterocytes that line brush border of small intestine, triglycerides resynthesized under control of several enzymes prior to incorporation into CM, transported via lymphatic so and on into bloodstream, acquire apoproteins from HDL after release in bloodstream
Fat transportation - lipoproteins (lipoprotein lipase)
Binds to CMs, located on capillary endothelial cells lining variety of tissues (ie adipose, heart and skeletal muscle), CMs travel from intestinal lacteals to thoracic duct and to left subclavian vein (bloodstream entry), fatty acids undergo beta oxidation, glycerol returned to liver for gluconeogenesis
Fat transportation - lipoproteins (general)
Transport hydrophobic molecule in aqueous environment, phospholipid monolayer with cholesterol and apoproteins surrounding core of cholesterol esters and triacylglycerol
Fat transportation - lipoproteins (cholesterol esters)
Synthesised in plasma from cholesterol and acrylic chain of phosphatidylcholine via reaction catalysed by lecithin, cholesterol acyltransferase (LCAT), pack more tightly in lipoprotein
Fat transportation - lipoproteins (HDL)
“Good cholesterol”, take cholesterol from peripheral tissues back to liver for use/disposal (reverse cholesterol transport), lower total serum cholesterol
Fat transportation - lipoproteins (LDL)
“Bad cholesterol”, prolonged elevation of LDL levels = atherosclerosis, opposite path to HDL, 40% cholesterol ester
Beta oxidation - general
Caloric yield from fatty acids = 2x carbs on weight basis, >1/2 of body’s energy needs (including liver but not brain), enhanced during fasting over long time periods, in mitochondria, result in acetyl-CoA
Beta oxidation - primary carnitine deficiency
Autosomal recessive, 1/100000 USA vs 1/40000 Japan vs 1/500 Faroe, symptoms in infancy/early childhood, encephalopathies+cardiomyopathies+muscle weakness+hypoglycaemia, mutations in gene SLC22A5 = reduced ability of cells to take up carnitine, Carnitor/Levocarnitine
Beta oxidation - cycle
Acyl CoA undergoes sequence of oxidation + hydration + thyolysis reactions to preoducd 1 molecule of acetyl CoA and acyl CoA species 2C shorter than original, continue to consecutively remove 2C from acyl CoA, on final cycle (4C fatty acyl CoA intermediate) 2 acetyl CoA molecules, 7 beta oxidation reactions = 16 C palmitoyl CoA = 8 acetyl CoA, each cycle = molecule of FADH2 and NADH
Beta oxidation - of palmitoyl CoA
Palmitoyl CoA + 7FAD + 7NAD+ + 7H2O + 7CoA -> 8 acetyl CoA + 7 FADH2 + 7NADH
Beta oxidation - acetyl CoA entering TCA cycle
Only if beta oxidation and carbohydrate metabolism are balanced since oxaloacetate is needed for entry, when fat breakdown predominates acetyl-CoA forms acetoacetate, D-3 hydroxybutyrate and aceton (ketone bodies)
Lipogenesis - general
Acetyl CoA and fatty acid synthase, formed sequentially by decarboxylatibe condensation reactions involving acetyl- and malonyl-CoA, following each round of elongation fatty acid undergoes reduction and dehydration by sequential action of ketoreductase (KR) + dehydratase (DH) and end reductase, growing fatty acyl group linked to an acyl carrier protein (ACP), acetyl CoA (C2) + 7 malonyl CoA (C3) + 14NADPH + 14H+ -> palmitate (C16) + 7CO2 + 6H2O + 8CoA-SH + 14NADP+, elongation of acyl group to make fatty acids longer than 16C occurs separately from palmitate synthesis in mitochondria in endoplasmic reticulum, desaturation of fatty acids requires fatty acyl-CoA desaturates, enzyme that creates oleic acid and palmitoleic acid from stearate and palmitate = delta-9 desaturase (generates double bond nine carbons from terminal carboxyl group)
Lipogenesis - cancer
de novo fatty acid biosynthesis restricted mainly to liver + adipose tissue + lactating breast, for energy source (hypothesis)
Lipogenesis - beta oxidation disorders
Family of different acyl-CoA-dehydrogenase catalyse initial step in each cycle of beta oxidation, each can bind a fatty acid chain of varying length (short-chain acyl-coenzyme A dehydrogenase (<6C), medium-chain (C6-C12), long chain (C13-C21), very long chain (>22C))
Lipogenesis - deficiency of medium chain fatty acids
MCADD, autosomal recessive, predominantly Caucasian, 1/10000 per year UK, if undiagnosed can be fatal, thought to account for 1/100 deaths from sudden infant death syndrome (SIDS), if diagnosed never go without food longer than 10-12 hours and adhere to high carb diet, patients with illness resulting in appetite loss/severe vomiting may need iv glucose to make sure body isn’t dependent on fatty acids for energy
