MBC - Cell Metabolism 2

Question 1

Five main lipid classes

Answer 1

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

Question 2

Fat transportation - Metabolism

Answer 2

Acetyl CoA production, most cellular oxidation reactions + ATP (cellular), beta oxidation

Question 3

Fat transportation - 3 primary sources

Answer 3

Diet, de novo biosynthesis (liver, lipogenesis), adipose storage deposits

Question 4

Fat transportation - bile salts

Answer 4

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)

Question 5

Fat transportation - orlistat

Answer 5

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

Question 6

Fat transportation - lipoproteins (categories)

Answer 6

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)

Question 7

Fat transportation - lipoproteins (chylomicron)

Answer 7

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

Question 8

Fat transportation - lipoproteins (lipoprotein lipase)

Answer 8

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

Question 9

Fat transportation - lipoproteins (general)

Answer 9

Transport hydrophobic molecule in aqueous environment, phospholipid monolayer with cholesterol and apoproteins surrounding core of cholesterol esters and triacylglycerol

Question 10

Fat transportation - lipoproteins (cholesterol esters)

Answer 10

Synthesised in plasma from cholesterol and acrylic chain of phosphatidylcholine via reaction catalysed by lecithin, cholesterol acyltransferase (LCAT), pack more tightly in lipoprotein

Question 11

Fat transportation - lipoproteins (HDL)

Answer 11

“Good cholesterol”, take cholesterol from peripheral tissues back to liver for use/disposal (reverse cholesterol transport), lower total serum cholesterol

Question 12

Fat transportation - lipoproteins (LDL)

Answer 12

“Bad cholesterol”, prolonged elevation of LDL levels = atherosclerosis, opposite path to HDL, 40% cholesterol ester

Question 13

Beta oxidation - general

Answer 13

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

Question 14

Beta oxidation - primary carnitine deficiency

Answer 14

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

Question 15

Beta oxidation - cycle

Answer 15

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

Question 16

Beta oxidation - of palmitoyl CoA

Answer 16

Palmitoyl CoA + 7FAD + 7NAD+ + 7H2O + 7CoA -> 8 acetyl CoA + 7 FADH2 + 7NADH

Question 17

Beta oxidation - acetyl CoA entering TCA cycle

Answer 17

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)

Question 18

Lipogenesis - general

Answer 18

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)

Question 19

Lipogenesis - cancer

Answer 19

de novo fatty acid biosynthesis restricted mainly to liver + adipose tissue + lactating breast, for energy source (hypothesis)

Question 20

Lipogenesis - beta oxidation disorders

Answer 20

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))

Question 21

Lipogenesis - deficiency of medium chain fatty acids

Answer 21

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