lipids Flashcards
what are the functions of lipids?
- energy store
- structural function (e.g. cell membranes)
- important signalling molecules
what are the essential FA in the body? (2)
- omega-3/a-linolenic acid (ALA) (required for DHA synthesis)
- omega-6/linolenic acid (LA) (required for AA synthesis)
what are fatty acids?
carboxylic acids w long aliphatic chains (saturated/unsaturated)
what are saturated fatty acids?
- “anoic”
- single bond in aliphatic chain, straight hydrocarbon chain
- allows close packing of molecules→ maximise SA for intermolecular interactions→ higher mp/bp
what are unsaturated fatty acids?
- “enoic”
- > =1 double bond in aliphatic chain, bent hydrocarbon chain
- kinked→ disrupts packing among molecules→ decrease SA for intermolecular interactions→ lower mp/bp
what are cis forms of unsaturated fatty acids?
- naturally occurring
- hydrocarbon chains are on the same side as the double bond
what are trans forms of unsaturated fatty acids?
- mostly generated through hydrogenation in food industry
- large consumption of trans fat→ increase low-density lipoprotein, decrease HDL→ increase atherosclerosis risk
what are triacylglycerol/triglycerides (TAG/TGs)?
glycerol backbone + 3 fatty acids (variable length, saturated/unsaturated)
where are TAGs/TGs synthesized? (2)
- liver: exports to extra hepatic organs
- adipose tissue: stored during fed state
how are components of TAGs/TGs synthesized?
glycerol
liver: direct glycerol uptake (fr CM) or fr DHAP (fr diet: glucose→ DHAP→ glycerol-3-phosphate)
adipose tissue: fr DHAP
fatty acids (x3)
liver: de novo synthesis fr glucose
adipose tissue: uptake (dietary and hepatic)
what is the composition of dietary lipids?
10%: cholesterol, cholesterol esters, phospholipids, fatty acids
90%: TAG
how are TGs/cholesterol esters/phospholipids digested?
TG: ingual/gastric/pancreatic lipase (TG→ glycerol + 2FA)
cholesterol ester: pancreatic esterase (CE→ cholesterol + FAs)
phospholipids: pancreatic phospholipase A2 (phospholipid→ lysophospholipid + FA)
what is the function of colipase?
- secreted into intestinal lumen w pancreatic enzymes
- counters displacement of lipase by bile salts at micelles→ anchors lipase @ lipid-aq interface→ increase activity of pancreatic lipase
what is the MOA of a drug that targets lipases for obesity control? + what supplement
orlistat
- irreversible inhibitor of gastric & pancreatic lipases→ decrease digestion/absorption of TGs→ excrete undigested TGs in feces
- also decreases fat soluble vitamin absorption→ needs vit ADEK supplements
what are the hormones released by the small intestine for lipid digestion? (2)
- CCK: stimulate bile salt + pancreatic lipase/colipase secretion
- secretin: stimulate HCO3- release from pancreas→ neutralise acidic chyme from stomach→ provides optimal pH for pancreatic digestive enzymes to work
what happens to lipids after absorption into small intestine? (3)
- reform initial lipids:
- monoacylglycerol + 2FAs→ TAG
- cholesterol + FA → cholesterol ester
- lysophospholipid + FA→ phospholipid - formation of nascent chylomicron
- TAG, cholesterol esters, phospholipid + fat soluble vitamins→ form nascent chylomicron
- ApoB-48 (produced by enterocytes) required for proper assembly of chylomicron - export into lymphatic system
- chylomicron transport out of enterocyte to lymphatics via exocytosis
what is the structure of lipoproteins eg chylomicrons?
outer layer
- single layer phospholipid: phosphate group face out; hydrophobic FA chains face inward
- embedded apolipoproteins: essential in structure, metabolism & function of lipoprotein particles
core (lipids)
- TAG, cholesterol esters
how do nascent CM get converted to mature CM?
- movement from lymph nodes (nascent) into blood (mature)
- HDLs in blood transfer apolipoproteins ApoE and ApoCII to nascent chylomicrons→ mature
what are the apoproteins on mature vs nascent chylomicrons?
nascent: ApoB48
mature: ApoCII, ApoE, ApoB48
what happens to mature chylomicrons in the blood? (4)
- ApoCII (LPL cofactor) activates LPL at capillary walls of muscles/adipose tissues (LPL synthesized & secreted by insulin)
LPL: TG→ FAs + glycerol - FA get taken up by muscles (→ATP) and adipose tissues (→TG for storage), glycogen by liver (lipogenesis)
- chylomicron remnants are taken up by liver (by ApoE)
- chylomicron remnants→ [lysosomal enzymes]→ FAs, glycerol, AA, cholesterol→ used by hepatocytes
nascent CM vs mature CM vs CM remnants? (2)
- apolipoproteins:
nascent: ApoB48
mature: ApoB48, ApoE, ApoCII
remnants: ApoB48, ApoE - CM remnant has low TG! (broken down to FA & glycerol by LPL)
what is hyperchylomicronemia?
- LPL or ApoCII deficiency→ impair TG hydrolysis in mature CM→ high lvl of CM→ severe hypertriglyceridemia→ xanthomas (lipid buildup under skin due to foam cells)
what are the main differences between chylomicron and VLDL? (2)
- apolipoproteins: ApoB48 (CM) vs ApoB100 (VLDL)
- TG content: dietary (CM) vs hepatic (VLDL)
what are the similarities between CM and VLDL (2)
- apolipoproteins: ApoCII and ApoE
- function: both deliver TG to extrahepatic tissues
how are fatty acids synthesised?
- from glucose→ glycolysis→ TCA cycle→ citrate→ [ATP citrate lyase]→ acetyl CoA→→→ LCFA-CoA
- in hepatocytes cytoplasm
what is the rate limiting enzyme of FA synthesis?
acetyl-coa carboxylase
how does FA synthesis get regulated after a meal?
insulin (hormone)→ upregulate Acetyl-CoA carboxylase→ upregulate FA synthesis
how does FA synthesis get regulated during fasting/exercise?
glucagon/epinephrine→ inhibit acetyl-coa carboxylase→ downregulate FA synthesis→ glucose conserved for energy production
how is FA synthesis allosterically regulated? (2)
citrate: upregulate
LCFA-CoA: downregulate (pdt inhibition)
what is steatosis + pathophysiology? (3)
accumulation of TG in hepatocyte vacuoles (fatty liver)
- AFLD, NAFLD
- increase FA synthesis→ increase TG synthesis
- TG synthesis rate> VLDL synthesis rate→ little TG exportation fr liver→ accumulates
- impaired VLDL secretion
what is the function of VLDL?
to deliver hepatic TAG to extra-hepatic tissues (FA of TAG in VLDL are synthesized by hepatocytes via de novo lipogenesis)
how is VLDL formed?
synthesized in the liver→ secreted to blood as nascent VLDL (contains ApoB100)→ acquire ApoE & ApoCII fr HDL→ mature VLDL
how does mature VLDL progress to IDL?
ApoCII on mature VLDL activates LPL at capillary wall of muscles/adipose
LPL converts TG→ FA + glycerol
FA: taken up by muscles (→ATP) and adipose tissues (→ TG for storage)
glycerol: taken up by liver
VLDL→ IDL (less TG→ increase density)
compare nascent/mature VLDL to IDL to LDL (3)
- apolipoproteins:
nascent VLDL: ApoB100
mature VLDL: ApoB100, ApoE, ApoCII
IDL: ApoB100, ApoE
LDL: ApoB100 - TG levels:
nascent/mature VLDL: same
IDL: low TG (broken down to FA & glycerol by LPL)
LDL: no TG (removed by HTGL) - cholesterol/cholesterol esters (all contain same amt :)
what happens to IDL? (2)
- forms LDL:
- transfers ApoE to HDL
- removes TG by hepatic triacylclycerol lipase (HTGL) - binds to APoER on hepatocytes→ endocytosis→ degraded
what happens to LDL? (2)
- ApoB100 binds to LDLR on hepatocytes→ endocytosis→ degraded
- taken up by extra-hepatic tissues via ApoB100 binding to LDLR→ delivers cholesterol/CE
how is LDL uptake by extra-hepatic tissue regulated?
sufficient cholesterol→ downregulation of LDLR→ decrease LDL/cholesterol uptake
what can go wrong with LDL uptake by extra-hepatic tissues?
e.g. lack of LDLR on liver: LDL can get oxidised in blood circulation→ taken up by scavenger receptors on macrophages→ foam cells→ atherosclerosis
what is the function of HDL? (2)
- transfers ApoCII and ApoE to nascent chylomicrons and nascent VLDLs→ mature :)
- reverses transport of C/CE fr extrahepatic tissue to liver
nascent HDL is synthesised in liver/small intestines
how does HDL directly reverse C/CE transport? (3)
- HDL take up C fr extrahepatic tissues, convert to CE
- lipid-rich HDL (HDL2) bind to SR-B1R on liver→ release C/CE, TG removed by HTGL
- lipid poor HDL (HDL3) released, continue picking up more C from extrahepatic tissues
how does HDL indirectly reverse C/CE transport? (3)
- HDL exchange CE for TG with VLDL via CETP (cholesterol ester transfer protein)
- loss of TG converts VLDL→IDL→ LDL
- IDL and LDL can transport CE back to liver via ApoER and LDLR-mediated endocytosis respectively
what is the difference in the transfer of cholesterol from HDL to liver vs LDL/VLDL?
- direct HDL transfer DOES NOT require endocytosis of whole lipoprotein
- indirect IDL/ LDL transfer require endocytosis of whole lipoprotein
how are FAs stored in adipose tissue?
- stored as TG (glycerol + FA)
FA: insulin stimulates LPL synthesis/secretion→ ApoCII (VLDL, CM) activate LPL→ FA taken up by adipose tissues, glycerol taken up by liver
glycerol: insulin activates glycolysis of glucose→ DHAP→ G3P (TG backbone)
how is lipolysis regulated during fasting state?
glucagon→ activates HSL (hormone sensitive lipase)→ converts TG to FAs + glycerol→ FAs transported as FA-albumin in blood to liver and muscles, glycerol transported to liver
why is long chain FA a good energy source? (2)
- oxidation produces fatty acyl-CoA that allows further rounds of oxidation→ produce more acetyl CoA
- oxidation of fatty acyl-CoA also produces FADH2 and NADH→ ETC→ ATP production
how is FA oxidation and lipogenesis regulated after feeding?
increase glucose→→→ citrate→ acetyl CoA→ [ACC]→→ malonyl CoA→ FA synthase→ increase lipogenesis
malonyl CoA is negative allosteric modulator of CPT1→ inhibits FA oxidation
what are ketone bodies? (3)
- acetoacetate
- B-hydroxybutyrate
impt energy fuel for extrahepatic tissues - acetone
where are ketone bodies produced/ketogenesis?
produced in the mitochondria of hepatocytes
what is the purpose of ketogenesis?
to produce ketones thats can be broken down (ketolysis) under fasting conditions to generate acetyl CoA→ TCA cycle→ ATP generation
how does ketogenesis occur? (2)
fasting→ glucagon!!
1. glucagon inhibits ACC (FA synthesis)→ no malonyl CoA→ increased B-oxidation (FA breakdown)→ generates acetyl CoA
2. glucagon upregulates HSL→ converts TG to FA & glycerol (lipolysis)→ FA-albumin travels into liver→ catabolysed to acetyl CoA
acetyl CoA enters ketogenesis pathway in the liver
where does ketolysis occur?
mitochondria of extrahepatic tissue (liver don’t have 3-ketoacyl-CoA transferase needed for ketolysis)
how does ketolysis occur?
ketone bodies move into extrahepatic tissues→ undergo ketolysis→ generates acetyl CoA→ TCA cycle→ ATP generation :)
how does type 1 DM cause ketoacidosis?
type 1 DM→ low insulin, high glucagon→ stimulates HSL (lipolysis)→ increase FA→ increase B-oxidation in liver→ increase acetyl CoA→ increase ketogenesis→ ketogenesis»ketolysis→ ketoacidosis→ ketonuria
what is the function of cholesterol?
- maintains cell membrane rigidity & fluidity
- precursor for key molecules synthesis e.g. bile acids, vit D, steroids
what are the sources of the hepatic cholesterol pool? (3)
cholesterol is stored in liver
1. dietary cholesterol (chylomicron remnants)
2. de novo synthesis in the liver
3. cholesterol from extrahepatic tissues (reverse cholesterol transport by HDL)
what happens to the cholesterol in the hepatic cholesterol pool? (3)
- transported in VLDL/IDL/LDL
- converted to bile acids/salt
- small amount excreted in bile
where does cholesterol synthesis take place?
- occurs in the liver (cytoplasm & ER)
- all carbons are derived from acetyl CoA
what is the rate limiting step of cholesterol synthesis?
HMG-CoA reductase
how is cholesterol synthesis regulated by hormones? (2)
anabolic process→ should only be activated if nutrients are readily available (not when limiting)
insulin:
- upregulate chol synthesis
- activates phosphatase→ dephosphorylate (activate) HMG-CoA reductase
glucagon:
- inhibit chol synthesis
- activate protein kinase→ phosphorylate/deactivate HMG-CoA reductase
how is cholesterol synthesis allosterically regulated? (2)
AMP (low ATP): activates AMP-activated protein kinase→ phosphorylates/deactivates HMG-CoA reductase
phosphatase: dephosphorylates/activates HMG-CoA reductase
how is cholesterol used in the synthesis of bile acids?
cholesterol→ [7a-hydroxylase]→→ primary bile acid→ feedback inhibition
how is cholesterol used in the synthesis of vit D3?
7-dehydrocholesterol (immediate precursor of cholesterol)→ [uv light]→ cholecalciferol (Vit D3, fr diet)→→ calcitrol (active vit D3)
