Lipids Flashcards
Do plant sources of lipids contain cholesterol?
No
Lipids all contain a (hydrophilic/hydrophobic group) making them water (soluble/insoluble)
Hydrophobic → Water insoluble
What are 3 functions of lipids?
1) Energy store
2) Structural function
3) Signalling molecule
FA are carboxylic acids with long ____________ chains and can be _________ or__________- depending on the presence of C=C. They are categorized based on __________.
Long aliphatic chain
can be saturated or unsaturated (have C=C)
Categorised based on length
Very long chain FA (VLCFA): 22 C or more
Long chain FA (LCFA): 14-20 C (most common)
Medium chain FA (MCFA): 8-12 C
Short chain FA (SCFA): 4-6 C
Most FAs have (even/odd) number of carbons.
Even
Naturally occurring unsaturated FAs have primarily (cis/trans) C=C.
Cis
A saturated FA has a (straight/bent) chain, therefore allowing for (maximal/reduced) surface area for intermolecular interactions, granting them a (higher/lower) m/b.p.t.
Saturated: usually animal sources
- Straight → Max SA for FOA → higher m/b.p.t.
(Unsaturated: usually plant sources
- Bent → ↓SA for SOA → ↓m/b.p.t.)
How are cis unsaturated FAs different from trans?
1) Cis: Hydrocarbons chains same side as double bond
Trans: opposite
2) Cis: Naturally occurring
Trans: Hydrogenation (↓prone to rancidity → ↑shelf life)
3) Trans: ↑LDL ↓HDL → ↑atherosclerosis risk
How are TG/TAGs digested?
By lipases (mainly pancreatic)
Triacylglycerol → Monoacylglycerol + 2 FA
How are cholesterol esters digested?
By Pancreatic esterase
Cholesterol ester → Cholesterol + FA
How are phospholipids digested?
By pancreatic phospholipase A2
Phospholipid → Lysophospholipid + FA
Lipids are firstly digested by _____________ which are most active in the stomach (low pH). They are then mostly digested in the _________, mediated by _______________, forming micelles and ______________ to be absorbed into enterocytes.
1st digested by lingual and gastric lipase (both most active in stomach)
Mostly digested in small intestine, mediated by:
i) Bile salts → emulsify to form micelles
ii) Pancreatic enzymes (lipase, esterase, phospholipase A2)
Bile salts are amphipathic molecules synthesised in the _______ and stored in the __________, where is can be released into the intestines to emulsify (i) ________ and (ii) ________, forming micelles to increase the surface area of lipid droplets for enhanced interaction with enzymes.
Synthesised in liver, stored in gall bladder
Emulsify (i) lipids and (ii) lipid-soluble vitamins
Lipases in intestinal lumen requires ______________ to aid in lipid digestion as __________________.
Colipase
- anchor pancreatic lipase to lipid-aqueous interface of micelles
- remove inhibitory effect of bile salts on lipase
What are 2 hormones that regulate lipids digestion in the intestines?
1) CCK
- ↑ CCK → ↑gall bladder + pancreatic secretion
2) Secretin
- ↑ secretin → ↑HCO3- from ductal cells → ↑pH for optimal enzyme digestion
How does an irreversible inhibitor of lipases eg. Orlistat help in obesity control?
↓digestion of TGs → excreted in feces rather than metabolised
Which vitamins should be supplemented in a px taking irreversible lipase inhibitors (eg. Orlistat)?
ADEK
- ↓digestion → ↑excretion of TGs in feces along with fat-soluble vitamins
→ need to supplement to compensate for ↓absorption
What are 3 causes of steatorrhea?
↓ Lipid digestion/absorption:
1) Bile salt deficiency
2) Pancreatic insufficiency
3) Disease affecting Small intestine → ↓abs
What is Steatorrhea?
Excessive fats in stools (fatty, floating)
How does fat-soluble vitamin deficiency present?
A: ↓retinol → ↓vision, immune f(x)
D: ↓Ca and ↓PO4 Abs → Osteomalacia
E: antioxidant → ↓oxidative stress
K: ↓coagulation factors, 2,7,9,10 deficiency → coagulopathy
How are (i) short/medium chain FAs (ii) micelles (iii) Bile salts absorbed into enterocytes?
i) Short/medium chain FAs → soluble, direct Abs
ii) Micelles → interact w cell membrane → lipid soluble contents diffuse into cell
iii) Bile salts → resorbed @ terminal ileum
How are absorbed lipids transported into circulation?
1) Conversion of digested lipids back into original form
- 2-Monoacylglycerols (2-MGs) + FAs → triacylglycerols (TAGs)
- Cholesterol + FAs → cholesterol esters
- Lysophospholipids + FA → Phospholipids
2) Formation of nascent chylomicrons
- need ApoB-48 (produced by enterocytes)
3) Exocytosis of nascent chylomicron into lymphatics
4) Lymphatics → blood circulation
What are lipoproteins?
Spherical macromolecule
Core: Lipids
Coat: monolayer of phospholipid
- have apolipoprotein associated
How are nascent chylomicrons converted into mature chylomicrons?
HDLs transfer (i) ApoE and (ii) ApoCII to nascent chylomicron → mature
(formed 1-3hrs after meal, cleared >8hrs)
Why can’t nascent chylomicrons just enter blood system directly?
Too large to pass through fenestrations in blood capillaries but can fit through larger pores in lymphatic capillaries
How do mature chylomicrons transport dietary TGs to muscles and adipose tissue?
1) ApoCII (from HDLs) → cofactor for lipoprotein lipase (on capillary walls of muscles and adipose tissue, stimulated by insulin)
2) Lipase → (TG → FAs + Glycerol)
3) FAs taken up by muscle and adipose tissues
- muscle → oxidised → ATP
- adipose → TG → storage
What happens to (i) glycerol and (ii) chylomicron remnants after mature chylomicron is acted on by lipoprotein lipase?
(i) Glycerol (passive) uptake by hepatocytes via Aquaporin-9
ii) Mature chylomicron loses ApoCII
→ Chylomicron remnants (have ApoB-48 and ApoE)
→ taken up by liver via ApoE receptor
→ degraded by lysosomal enzymes
What is the pathogenesis of hyperchylomicronemia?
Genetic deficiency of (i) lipoprotein lipase (LPL) or (ii) ApoCII
→ ↓hydrolysis of TG in mature chylomicrons
→ HyperTG
→ Xanthomas on knees, butt, arms (build up of foam cells)
What should be the dietary recommendation for px with hyperchylomicronemia?
Low fat diet
(↓chylomicron synthesis)
De novo lipogenesis is the synthesis of FAs from __________ precursors.
Non-lipid (eg. carbohydrates)
How does glucose contribute to de novo FA synthesis in the liver?
1) Glucose → pyruvate (glycolysis in cytosol)
2) Pyruvate → Acetyl CoA (PDH) + Oxaloacetate (Pyruvate carboxylase)
- in mitochondria
3) Acetyl CoA → Citrate (Citrate synthase)
4) Citrate transported to cytosol
5) Citrate → Acetyl CoA + Oxaloacetate (ATP citrate lyase)
6) Acetyl CoA → DNL
What is the committed/rate limiting step of DNL?
Acetyl CoA → Malonyl CoA
- via Acetyl CoA Carboxylase
How is ACC in DNL regulated?
1) Allosteric
+: Citrate
-: LCFA CoA (-ve feedback)
2) Hormonal
+: Insulin
-: Glucagon and epinephrine
Fatty acid synthase is a multi-enzyme complex that converts Acetyl-CoA and Malonyl CoA into FA in the ________ of cells and its expression is induced by ____________ hormone.
Cytoplasm
Insulin
For TAG synthesis in the liver, where do (i) FAs and (ii) Glycerol come from?
FAs: DNL (from glucose)
Glycerol: Direct glycerol uptake (Mature chylomicrons) or DHAP (from glucose)
For TAG synthesis in the adipose tissue, where do (i) FAs and (ii) Glycerol come from?
FA: Uptake (dietary and hepatic)
Glycerol: From DHAP (from glucose)
How does the fate of TAG synthesised in the liver differ from that in the adipose tissue?
TAG in liver exported to other extra-hepatic organs.
TAG in adipose tissue stored during fed state.
How are VLDLs formed?
1) Synthesised (FA of TGs from DNL) and secreted from hepatocytes with ApoB100 as nascent VLDL
2) Nascent VLDL acquire ApoE and ApoCII from HDL → mature VLDL
What is the primary function of VLDL?
To delivery hepatic TAG to other tissues
What happens to VLDL after TG delivery?
Loss of TG and ApoCII (during TG delivery)
→ IDL
a) return to liver via ApoE receptor
b) remain in circulation and deliver more TG → LDL (via HTGL)
What are 3 key dysregulated biochemical features in hepatocytes?
1) ↑FA synthesis → ↑TG
2) Rate of TG synthesis»_space; VLDL synthesis → TG accumulation
3) Impaired VLDL secretion
How are TAG stores in adipose tissue after feeding?
After feed → ↑glucose → ↑insulin
a) ↑glucose uptake → glycolysis → DHAP → G-3-P for TAG synthesis
b) ↑Lipoprotein lipase exp. → ↑FA from VLDL/chylomicrons → Fatty acyl CoA for TAG synthesis
Describe how lipolysis is induced in adipocytes under fasting conditions.
Fasting → ↓glucose → ↑glucagon
→ HSL (hormone sensitive lipase)
→ (TG → FAs + Glycerol)
How are FAs transported in the blood?
As a FA-albumin complex (no need lipoprotein)
How are FAs transported into the mitochondria?
1) FA → FACoA in cytosol
2) FACoA + Carnitine → CPT1 transporter → into mitochondrial intermembrane space
3) FA-carnitine → CPT2 → FACoA into mitochondria + Carnitine back into cytoplasm
What is the rate limiting step for oxidation of fatty acids in the mitochondria?
Carnitine-mediated entry of FA into mitochondria
CPT 1 which is responsible of the transport of ___________ into the mitochondrial intermembrane space is inhibited by _______________.
CPT 1: FA transport (with Carnitine)
Inhibited by Malonyl CoA
How is FA ß-oxidation regulated after a heavy meal?
Heavy meal → ↑Glucose + ↑insulin
↑glucose → ↑Substrate for ACC
↑ Insulin → ↑ACC activity
→ ↑Malonyl CoA →inhibit CPT1
→ ↓transport of FA into the mitochondria for ß-oxidation
v.v. for ↓glucose and ↑glucagon
In FA ß-oxidation, ______ produces ___________ where it enters the TCA cycle or used for ketogenesis. This process produces ___________ and ____________.
Fatty acyl CoA → Acetyl CoA (until fatty acyl chain has no more Cs)
Produces NADH and FADH
Ketogenesis only occurs in the ________ under ______________ conditions in healthy individuals.
Mitochondria of hepatocytes
under fasting conditions
Which of the ketone bodies are important energy sources for extrahepatic tissues during periods of fasting?
1) Acetoacetate
2) ß-hydroxybutyrate
During periods of fast, what are the hormonal mechanism that supply high levels of acetyl CoA for ketogenesis?
Fasting:
a) ↑glucagon → HSL → ↑Lipolysis → FA-albumin → from adipocytes to liver
b) ↑glucagon + ↓insulin → inhibit ACC → ↓inhibition of CPT 1 → ↑ß-oxidation of FA
Both ↑Acetyl CoA
True or false:
Ketogenic amino acids are the main source of ketone bodies.
False
FAs are main source
Of the ketone bodies, ________ is volatile and can be smelt in the breath and is the least amount of the 3 ketone bodies.
Acetone (nail polish, sweet/fruity smell)
Does the liver carry out ketolysis?
No, no exp. of 3-ketoacyl-CoA transferase required for catabolism of ketone bodies
Why do px with Type 1 DM exhibit ketoacidosis?
Type 1 DM → destruction of ß-cells of pancreas
→ ↓insulin but ↑glucagon
→ ↑lipolysis (via HSL) + ↑ß-oxidation (↓inhibition of CPT via ↑inhibition of ACC)
→ rate of ketogenesis»_space; ketolysis
→ ketoacidosis (acidic and soluble)
→ ketonuria
What is a ketogenic diet?
High fat diet (4:1 by weight) of lipid:carbohydrate
What are 2 clinical applications of ketogenic diets?
1) ↓freq. of epileptic seizures in children
2) treat children w pyruvate dehydrogenase deficiency → fuel by brain in place of TCA
What are 2 functions of cholesterol?
1) Maintain cellular membrane and fluidity
2) Precursor for biosynthesis
(eg. bile acids, vit. D, steroid hormones)
What is the hepatic cholesterol pool and what are 3 cholesterol sources?
Liver
From:
1) Dietary (Chylomicron remnants
2) De novo synthesis
3) Extrahepatic tissues (reverse cholesterol transport by HDL)
What are 3 fates of cholesterol in the liver?
1) VLDL synthesis
2) Conversion into bile salts/acids
3) Secreted as free cholesterol in the bile
What is the moa of Ezetimibe (inhibitor of intestinal sterol absorption)?
Inhibit NPC1L1 transport (responsible for transporting cholesterol from intestinal lumen to enterocytes)
Usually Rx w Statins
Cholesterol and its derivates have a characteristic ______ (3 6C and 1 5C ring structure). If its has a _________ linked to it, it is known as a cholesterol ester.
Steroid nucleus
+ Fatty acid → Cholesterol ester
Where does stage 1 (Mevalonate synthesis) of cholesterol synthesis occur?
Cytoplasm and ER
Where are (i) HMG-CoA synthase and (ii) HMG-CoA reductase found in cells?
(i) HMG-CoA synthase: cytosolic
(ii) HMG-CoA reductase: ER membrane
What is the comitted step and rate limiting step of cholesterol synthesis?
HMG-CoA → Mevalonate
- via HMG-CoA reductase
How is cholesterol synthesis physiologically regulated?
At HMG-CoA by allosteric covalent modification
Low energy → ↑glucagon + ↑AMP
- AMPK activated by (i) AMP (ii) Glucagon
→ P HMG-CoA reductase → inactive
→ ↓cholesterol synthesis
High energy → ↑insulin
- Activate phosphatase
→ de-P HMG-CoA reductase → active
→ ↑cholesterol synthesis
What is the moa of statins?
Structural analogs of HMG-CoA → CI of HMG-CoA reductase
→ ↓mevalonate synthesis (rate limiting)
→ ↓ de novo cholesterol synthesis
→ ↓hepatic cholesterol pool
→ ↑exp. of LDL receptors on hepatocytes
→ ↑LDL uptake via receptor-mediated endocytosis
→ ↓risk of atherosclerosis
How is cholesterol catabolised?
Sike, it doesn’t.
How do cholesterol synthesis and ketogenesis not compete for HMG-CoA in hepatocytes?
Cellular compartmentalisation
1) Cytosol
- cholesterol synthesis
2) Mitochondria
- ketogenesis
How are primary bile acid synthesised?
Cholesterol → Cholic acid or Cenodeoxycholic acid
- via 7α-hydroxylase
How is primary bile acid production regulated?
Feedback inhibition
- primary bile acids → ↓exp. of 7α-hydroxylase
How are primary bile salts formed?
Primary bile acid conjugated w taurine or glycine → primary bile salts
Why do bile acids need to be conjugated to taurine or glycine?
To have a lower pKa
→ ↑deprotonated (conjugate base) form
→ ↑solubility
→ better emulsifiers
What is the difference between a bile salt and a bile acid?
Bile acid: protonated form of acid (eg. R-COOH)
Bile salt: salt of conjugate base (eg. R-COO-)
After digestion, most primary bile salts are actively reabsorbed at the ileum. What happens to the rest?
Intestinal bacteria convert some to secondary bile acids (by deconjugated and dehydroxylation)
→ 2° bile acids passively absorbed at colon
How are bile acids recycles?
Enterohepatic circulation:
- Liver produce bile salts → gall bladder → intestines
a) 1° actively reabsorbed at ileum
b) 2° (deconjugated and dehydroxylated by intestinal bacterial) passively reabsorbed at colon
→ both return to portal circulation
(only <5% excreted in feces)
What is the moa of bile salt resins eg. cholesyramine?
Bile acid sequestrants:
- binds to bile salts in intestines to form insoluble complex → excreted in feces
→ ↓recycling of bile acids
→ induce ↑cholesterol synthesis in liver
↓hepatic cholesterol pool
→ ↑exp. of LDL receptors on hepatocytes
→ ↑LDL uptake via receptor-mediated endocytosis
→ ↓risk of atherosclerosis
How is Vitamin D synthesised?
1a) 7-dehydrocholesterol→ UV exposure in skin → Vit. D3
or
1b) dietary Vit. D2/3 → Vit. D3
2) Transported to liver
Vit. D3 → 25-(OH)D3
3) 25-(OH)D3 → Active calcitrol/Vit. D3 in kidney
How does calcitrol (active vit. D3) aid in calcium absorption from the intestine?
Steroid hormone → diffuse into cell
→ bind to Vit. D receptor in cytoplasm
→ transported to nucleus
→ ↑exp. of genes for Vit. D action
→ ↑Ca transporters in intestine
What is the common precursor for all steroid hormones?
Cholesterol
What are 3 organ sites of steroid hormone synthesis?
1) Adrenal cortex
2) Testes
3) Ovarian follicle
Where is Lipoprotein Lipase located?
Capillary walls of muscles and adipose tissue
What is the function of ApoCII?
Cofactor of LPL → lipolysis
What are 2 fates of LDL?
1) Returned to liver via LDL receptors (ApoB100-LDL receptor)
2) Delivers cholesterols to extrahepatic tissues
What is the difference between Chylomicrons and VLDL?
1) Apolipoproteins
Chylomicron: ApoB48, ApoCII, ApoE
VLDL: ApoB100, ApoCII, ApoE
2) TAG content
Chylomicron: Dietary
VLDL: Hepatic
3) Function
Chylomicron: Deliver dietary TG
VLDL: Deliver hepatic TG
4) Fate of remnants
Chylomicron: Chylomicron remnants → liver
VLDL: IDL → liver/IDL → liver
What are 2 fates of IDL?
1) TG hydrolysed by HTGL + Transfer ApoE to HDL→ LDL
2) Taken up into liver via ApoE receptor (receptor-mediated endocytosis)
HTGL = Hepatic TG lipase (hepatic lipase)
What are the function of 3 apolipoproteins?
B100 → LDL receptor (Liver and peripheral cells)
ApoE → ApoE receptors (Liver only)
ApoCII → LPL coenzyme
In the pathogenesis of atherosclerosis, LDL can be ________ and taken u[p by scavenger receptors of ____________ leading to the formation of _______________.
Oxidised → Macrophages → Foam cells
Describe the role of LDL in atherosclerosis.
1) ↑LDL levels → can be retained/trapped at damages site of endothelium → oxidised LDL
2) Endothelial cells exposed to oxidised LDL → cytokines → accumulation of monocytes
3) Monocytes → macrophages → internalise oxidised LDL, cholesterol esters, cholesterol → foam cells
4) Foam cells accumulate → plaque → thicken and harden arterial wall (atherosclerosis)
5) Smooth muscle cells of artery replicate and migrate → firm cap covering plaque
Plaque can rupture → release of cytokines and thrombogenic agents → AMI or ischaemic stroke
Which 2 lipoproteins contain the higher % of TGs?
Chylomicrons and VLDLs
Which lipoproteins contain the highest % of cholesterol/cholesterol esters?
LDL
What is the process of direct reverse cholesterol transport by HDL?
1) Nascent HDL synthesis by liver and small intestine
2) HDL take up cholesterol from cell membrane of extrahepatic tissues and convert C to CE
3) Lipid-rich HDLs (HDL2) bind to SR-B1 on liver → release C/CE, TG is removed by HTGL
4) Resultant lipid-poor HDL (HDL3) released → pick up more C/CE from extra hepatic tissues
What is the process of indirect reverse cholesterol transport by HDL?
1) HDL exchange CE for TG with VLDL via CETP (CE transfer protein)
2) Loss of TG → (VLDL → IDL → LDL)
3) IDL (via ApoE) and LDL (via LDL receptor/B100) transport CE back to liver
What is the difference between direct and indirect reverse cholesterol transport by HDLs?
Direct: HDLs transfer C/CE/TG directly to liver via SR-B1 (C/CE) or HTGL (TG)
Indirect: HDLs exchange C/CE w TG with VLDL (via CETP) → transport back to liver in IDL (via ApoE) or LDL (LDL-receptor/B100 mediated endocytosis)
How does the transfer of lipids to the liver differ between (i) HDL and (ii) Chylomicron remnants, IDL, LDL?
i) HDL does not require endocytosis of whole lipoprotein
ii) Chylomicrons, IDL, LDL undergo receptor-mediated endocytosis
How are cholesterol/lipids measured for clinically (4)?
Fasting (overnight/10-14hr) blood sample:
1) TAG
2) Total cholesterol (HDL, LDL, VLDL)
3) LDL-cholesterol
4) HDL-cholesterol
Which of the lipoproteins are not routinely measured?
IDL and Chylomicrons
What is familial hypercholesterolemia?
Genetic mutation in LDL receptor gene (homo/heterozygous)
→ ↑LDL and LDL-cholesterol in blood
→ premature CHD, AMI, atherosclerosis
→ Xanthomas
What is the pathogenesis of familial hypercholesterolemia that leads to ↑LDL and LDL-cholesterol?
Genetic mutation in LDL receptor gene
→ cannot effectively induce normal LDL uptake into organs and tissues
→ accumulation of LDL in circulation
→ ↑ LDL-cholesterol in the blood
What is the moa of Fibrates?
Active transcription factor (PPAR-α) → ↑exp. of genes for lipid catabolism (eg. LPL, CPT1)
a) → ↑ FA catabolism
→ ↓liver TG by ↑ß-oxidation
→ ↓VLDL secretion
→ ↓LDL production from
b) ↑apolipoproteins of HDL and HDL synthesis
What is the difference between glycerophospholipids and sphingolipids?
Glycerophospholipids: Glycerol backbone
Sphingolipids: Spingosine backbone
What are 2 functions of phospholipids?
1) Structural (eg. lipoproteins, cell/mitochondrial membrane)
2) Cell signaling (eg. phosphatidylinositol)
What is the key phospholipid in myelin sheath?
Sphingomyelin
How are phospholipids catabolised?
By phospholipases
→ cleave into fatty acids, polar head group, etc.
(occur at cellular membranes)
What are 3 types of eicosanoids?
1) Prostaglandins
2) Thromboxanes
3) Leukotrienes
Eicosanoids are most frequently derived from ___________________ and acts as _____________ hormones.
Derived from arachidonic acid
Para/autocrine hormones
How are eicosanoids synthesised?
Stimuli (eg. inflammation, mitogenic)
→ activation and translocation of phospholipase A2 from cytosol to cell membrane
→ Membrane phospholipids containing arachidonic acid → cleaved by phospholipase A2
Arachidonic acid then used to synthesise eicosanoids
Where does arachidonic acid come from?
Synthesised from linoleic acid (essential fatty acid)
What are essential fatty acids?
FAs not synthesised by body but needed for health and must be obtained from diet.
(LCFAs with double bonds at ω-3 or ω-6 carbon → cannot be synthesised by humans)
Linoleic acid and α-linolenic acids are _________ fatty acids that are polyunsaturated. They are required for the synthesis of important fatty acids such as AA and DHA.
Essential
True or false.
EPA and DHA can be synthesised from ALA but is still recommended to be consumed in the diet due to their low conversion efficiency.
True
Arachidonic acid is synthesised from which essential fatty acid?
Linoleic acid (ω-6)
Docosahexaenoic acid (DHA) is synthesised from which essential fatty acid?
α-Linolenic acid (ω-3)
What are 4 actions of prostaglandins?
1) vasodilation
2) ↓platelet aggregation
3) Inflammation
4) ↑ Pain
5) Gastric mucosal barrier
What are 2 actions of thromboxanes?
1) ↑Platelet aggregation
2) Vasoconstriction
What is the action of leukotrienes?
Contraction of lung muscles
(Overproduction → inflammation in allergic rhinitis and asthma)
Why is aspirin (Acetylsalicylate) an irreversible COX inhibitor?
It acts by transferring an acetyl group to the serine residue on the active site of COX
Why does COX1 inhibition cause stomach ulcers?
COX1 (constitutively expressed in the gastric mucosa) → PGE2 (promotes gastric mucosal barrier)
Inhibition of COX 1 → ↓PGE2 synthesis → ↓cytoprotective effects
Why do COX2 selective inhibitors reduce the risk of stomach ulcers?
COX2 not expressed in the stomach
Why have some COX2 selective NSAIDs been withdrawn from clinical use?
Use was a/w heart attacks
- ↓PGI2 synthesis in endothelium → vasodilation and ↓platelet aggregation
