Lipids Flashcards
Phosphatidic acid
Head group = H
Cardiolipin
Two phosphatidic acids esterified to an additional glycerol molecule, FOUND ONLY IN INNER MITOCHONDRIAL MEMBRANE
Plasmalogens
Glycerophospholipids w/ C1 fatty acid attached via an ether linkage rather than an ester linkage, almost 30% of glycerophospholipids in the brain are plamalogens, reduced levels assoc. w/ Alzheimer’s
Phosphatidalethanolamine
Plasmalogens with unsaturated ether linkage at C1 FA
Platelet-activating factor
Plasmalogens with saturated ether linkage at C1 FA and acetyl group at C2 FA
Glycerophospholipids with net charge = 0
PC, PE, SM, because alcohol = +1
Glycerophospholipids with net charge = -1
PI, PG, PS, because alcohol = 0
Saturated fatty acid is?
Unsaturated fatty acid is?
C1, C2
Ceramide
Sphingosine + acyl tail
How is phosphatidic acid formed?
2 acyl transferace rxns with activated acyl CoA substrate and glycerol 3 phosphate (from DHAP)
How are PC and PE formed?
1) both formed form dephos of phosphatidic acid (diacylglycerol), followed by condensation with CDP-choline/ethanolamine
2) PC can be made by methylating PE using SAMx3
How is PI formed?
Dephos of phosphatidic acid (diacylglycerol), followed activation of CDP-diacylglycerol and addition of inositol
How is PS formed?
Base exchange between serine and PE, which requires PLP
Formation of glycerol-3-P from glycerol occurs where?
Only in the liver
Formation of glycerol-3-P from DHAP occurs where?
Liver and adipose
How is sphinganine formed?
PalmitoylCoA + serine in NADPH rq rxn
Phospholipases
degrade glycerophospholipids by hydrolyzing
phosphodiester bonds
lysophosphoglyceride
remaining molecule after one acyl chain is removed by a phospholipase, PLA1(mammalian tissues) and PLA2(mammalian tissues and snake and bee venom) make these
PL-C
acts on PIP2 to make DAG (activates PKC) and IP3 (Ca++ release), found in bacteria
SMase
Removes phosphorylcholine from sphingomyelin to form ceramide (sphingasine + acyl tail)
Niemann-Pick disease
AR, defects in lysosomal acid SMase, type A (5%) type C and D is defect in transport proteins not SMase, cherry-red macula, hepatosplenomegaly
Neutral glycosphingolipids
glucocerebroside, glucocerebroside, globoside attached to ceramide through O-glycosidic bond
Acidic glycosphingolipids
negatively charged at physio pH because of NANA in gangliosides (some serve at receptors for bacterial toxins - cholera) or sulfate in sulfatides
Synthesis of glycosphingolipids
Made in Golgi by sequential attachment of UDP-sugars by glycosyl transferases, sulfate groups are attached to galactose by a sulfotransferase using PAPS as the sulfate donor
Degradation of glycosphingolipids
internalized by endocytosis into lysosomes, sugars are removed one at a time by lysosomal hydrolases producing ceramide, which can be degraded to sphingosine and FA
Tay-Sachs
accumulation of GM2 because lacking b-hexosaminidase A enzyme, fatal, cherry-red macula, blindness
Gaucher disease
accumulation of glucocerebrosides because lacking b-glucosidase/glucocerebrosidase, most common lysosomal storage disease, hepatosplenomegaly, osteoporosis of long bones
Fabry disease
accumulation of globosides because lacking a-galactosidase
Eicosanoids derived from?
20C, unstaturated n-6 FAs, usually arachidonic acid, that is released from membrane by PLA2
Synthesis of prostaglandins and thromboxanes
Arachidonic acid to PGH2 by PGH
synthase, an enzyme with two catalytic activities: COX (forms the intermediate PGG2) in an O2-requiring reaction, and a peroxidase, (converts PGG2 to PGH2) in a glutathione-requiring reaction
COX1 vs COX2
COX1 is constitutively-expressed in most tissues, COX2 is induced by cytokines during inflammation
NSAIDs
inhibit production of all prostaglandins and thromboxanes
Celecoxcib
selective COX2 inhibitor, increase in cardiovascular side effects because of decrease PGI2
PGH2 is converted to?
PGI2 in endothelial cells
TXA2 in platelets
PGF2 and PGE2 in other cells
TXA2
produced by platelets, promotes platelet aggregation, vasoconstriction, contracts SM
PGI2
produced by endothelial cells, promotes vasodilation, inhibits platelet aggregation, inhibited by COX2 inhibitors
PGF2a
produced in most tissues, promotes vasoconstriction, contraction SM, uterine contraction
PGE2
produced in most tissues, promotes vasodilation, relaxes SM, used to induce labor
Leukotriene synthesis
Arachidonic acid to LTA4 and HPETE intermediate by 5-LOX, LTA4 can then be converted in mast cells and eosinophils to LTC, LTD, LTE that contain cysteinyl leukotrienes that form slow-reacting substance of anaphylaxis (SRS-A), and in neutrophils and monocytes to LTB that induces activation and adhesion of leukocytes on endothelium and chemoattractant for neutrophils
Palmitic vs palmitoleic which is sat vs unsat?
Palmitic is sat
Palmitoleic is unsat
Sphingomyelin is major component of?
Myelin sheath
PL-A are inhibited by what?
glucocorticoids
Gangliosides come from what?
Globoside + CMP-NANA
Sulfatides come from what?
Galactocerebrosides + PAPS
Difference between Aspirin and other NSAIDs
Aspirin binds irreversibly to COX1 (platelets) vs other NSAIDS are competitive inhibitors that are not perminant
Structural difference between prostiglandins/thromboxanes and leukotrienes
prostiglandins/thromboxaines have cyclic portion leukotrienes do not, longer 1/2 life
LTB4 function
increased chemotaxis of leukocytes, adhesion of WBCs, release of lysosomal enzymes, allergic reactions
formation of LTC4, D4, E4
made from LTA4 + glutathione, contain cysteine LTC4 most important for asthma symptomes, mediate SRS-A Slow reacting substance of anaphylaxis
Where are prostiglandins/thromboxanes and leukotrienes catabolized?
ALL catabolized in peroxisomes
Drugs that prevent asthma?
5-LOX inhibitors and antagonsits of CysLT1 receptor
Hydroxyl group at C3 of ring A?
Sterol
How much Cholesterol comes from diet vs synthesis
30% diet, 70% synthesis
Where do C’s from cholesterol come from?
Acetyl coA
Synthesis of cholesterol?
1) 2 acetyl CoA = acetoacetylCoA
2) acetoacetylCoA + acetylCoA = HMGCoA (HMGCoA synthase)
3) HMGCoA reduces to mevalonate 5C (HMGCoA reductase rqs NADPH - RL and Reg Step!!!!!!! inhibited by statins)
4) IPP 5C (costs 3ATP)
5) GPP 10C
6) FPP 15C***
7) Squalene 30C (18ATP
8) Lanosterol - ring closure step by ER-assocaited squalene monooxygenase
9) cholesterol
Isoforms of HMGCoA
cytosolic - precursor to cholesterol
MT - used to make ketone bodies
What can FPP funnel into?
ubiquinone (CoQ) for ETC, dolichol (N-linked glycosylation, prenylated proteins (adding lipid tail)
Transcriptional control of HMGCoA
SREBP-2 binds SCAP which binds Insig in ER membrane if sterols are high
SCAP senses sterol levels
when sterols are low, SCAP doesnt assoc with Insig and SREBP-2 SCAP goes to golgi, where S1P and S2P cleave SREBP-2 to active amino-terminal domain TF
Genes upregulated by SREBP-2
HMGCoA reductase, LDL-R and PCSK9
SREBP-1?
regulates FA synthesis in a similar way to SREBP-2
Proteosomal degredation of HMGCoA
HMGCoA binds Insig in ER, ubiquitination and proteosomal degr.
HMGCoA phos/dephos
HMGCoA-P (inactive) with high levels of AMPK (AMP), HMGCoA activated by phosphatase
Hormone regulation of HMGCoA
Insulin - active, via increased phosphatase
Glucagon - inactive, via increase AMPK
Thyroxine - increased synthesis
Glucorticoids - decrease synthesis
Rate limiting step of bile acid production? What follows?
addition of -OH to B ring by cholesterol-7-a-hydroxylase (phase 1)
followed by phase 2 addition of glycine/taurine and secreted into ilium of intestines
Almost all bile salts are?
Reabsorbed (95%)
17-a-hydroxylase deficiency
no androgens or cortisol produced, increase mineral corticoids (aldos) increase Na retention/edema, pts have female genitalia
21-a-hydroxylase deficiency
no mineral corticoids (aldos), get salt wasting and no cortisol, make more androgens, masculinization of external genitalia in females
Testosterone to estradiol?
enzyme: Aromatase (CYP 19)
Order of lipoproteins for density, % lipid, % TG, %protein, electrophoresis?
Density: CM, VLDL, IDL, LDL, HDL %PL: CM, VLDL, IDL, LDL, HDL % TG: HDL, LDL, IDL, VLDL, CM % Protein: CM, VLDL, IDL, LDL, HDL Electrophor (-) to (+): CM, LDL, VLDL, HDL
CM have what?
ApoB48 vs ApoB100 in VLDL and LDL
Microsomal triacylglycerol transfer protein (MTP)
loads ApoB48 with lipid in ER for CM
necessary for loading TG to VLDL/CM
w/o MTP deficient in fat sol vit: ADEK because couldnt package them for distribution
Abetalipoproteinemia
No MTP, cant make CM or VLDL
Synthesis of CM
MTP loads ApoB48 with lipid in ER, moves to golgi, secreted to lymphatics then blood at nascent CM stage, in plasma gets ApoC-II and ApoE from HDL, ApoCII activates LPL on endothelia cells of caps (except liver), removal of TGs, ApoCII leaves to give CM remnant, ApoE stays and is the ligand receptor in liver, where remnant is degraded
Lifetime of CM?
few hrs
VLDL
carries TG to perifery, apoB100, produced in liver, need MTP, when TAGs are removed becomes IDL, when ApoC and ApoE level, becomes LDL
CETP
TAGs transferred from VLDL to HDL for cholesteryl esters from HDL to VLDL
LDL
carries CE/C to periphery and liver, want <100 LDL-R recognizes ApoB100 and not B48, and have higher affinity for ApoE on IDLs than ApoB100, receptor binding leads to endocytosis, drop in pH to separate receptor and keep LDL, return receptor to surface
ACAT
esterfiest cholesterol with FA for better storage
PCSK9
blocks LDL-R recycling to cell surface
FH
AD, AA - 4-6x normal, Aa - 2-3x normal serum cholesterol
Statins vs sequenstrins
Statins inhibit HMGCoA reductase, sequestrins makes you excrete bile acids, so you make more by increasing HMGCoA and LDL-R, should be given together!
HDL
formed by lipids + ApoA1 (produced by liver and intestines), removes cholesterol from periphery to liver, want >60
ABCA1
releases cholesterol that is taken up by HDL
LCAT
activates ApoA1 on HDL, more discoidal shape, binds to SR-B1 in liver
Friedewald equation
LDL = Total - HDL - TG/5 (VLDL)
risk factors for atherosclerosis
Sex (male), family Hx of atherosclerosis, hypertension, hypothyroidism, obesity (abdominal), increasing age, smoking, low physical activity, and a diet high in cholesterol and saturated fats
Type 3 hyperlipidemia (dysbetapiloproteinemia)
xanthomas at palmar crease, floating LDL on electropho, receptor defective apoE
Type 1 Hyperlipidemia
increased CM, LPL/apoCII deficiency, Eruptive xanthomas (lipid deposits in skin b/c Macrophages phago CM, local to butt, knees and extensor surface of arms)
disease associated with ApoE4
late onset form of Alzheimers disease
Type 2a Hyperlipidemia
increased LDL, polygenic or familial, xanthomas on extensor tendons of hands and achilles tendons and ocular lipid deposits - corneal arcus
Type 5 Hyperlipidemia
increased VLDL and CM, LPL/apoCII deficiency
Where are VLDL made? and then where do they go?
RER on liver and post translationally modified by adding CHO, combine with products of lipid syn, pass through secretory pathway to golgi
Low Lecitin/sphingomyelin
Need surgactant therapy as DPCC is lacking that is needed to reduce surface tension to prevent collapse of alveli (fetus doesnt have DPCC, risk of respiratory distress syndrome)
Tay-Sachs
accumulate GM2 because lacking hexoseamindase
Neimann Pick
deficiency of sphingomylinase, cant degrade sphingomyline to cermide
All sphingolipidoses are?
lysosomal storage diseases, AR defect in lysosomal enzyme
Gauchers common symtomes
hepatomegalyy, splenomegaly, bruising, low platelets, anemia, osteopina, Ashkenzi jewish prevalent
PGI2 has how many double bonds?
double bonds - cox# = 2
Enzymes that play a role in asthma?
LTC4
Ductus arteriosus is due to?
PGE2
Can sterol nucleus be catabolized?
not degraded or catabolized, must be secreted, cant be broken down for energy/down to Acetyl coA
-OH is on what ring in cholesterol
C3 of A ring
unsaturated ring in cholesterol?
B/2nd ring, C5-6
Fatty Acid syn occurs where?
Liver
B-ox occurs where?
MT
Cholesterol syn occurs where?
cytosol, but HMGCoA Reductase in SER
No HMGCoA Reduct, downstream issues?
No FPP thereofre GPI anchors, ETC and RAS will be messed up, and no Vit D from 7-dehydrocholestrol, issues with skin, also steroid hormones syn and bile acids syn
Mutation in Ras proto-oncgo
gain of function, uncontrolled cell growth
LDL receptor is degraded
FALSE- recycled
Normal Cholesterol, LDL, HDL, TG
60, <150
What do statins affect?
Everything downstream of HMGCoA reductase
Gain of function vs loss of function mutation in PCSK9
gain - increased degradation of LDL-R, more blood LDL
loss - increase LDL-R, decrease blood LDL, lower blood LDL, and risk of CHD
Use of statins and sequenstrins together does what?
Forces liver to make bile acids from blood cholesterol, lowering [ ]
PAPS relation to steroid hormones
PAPS sulfates steroid hormones, making them more water sol, less tightly bound to binding proteins and can be filtered out of blood by kidney
Metformin acting on VLDL and TG?
increases AMPK so insulin cant upreg. SREBP1 in liver for FA syn, so cant make FA, lowers TG levels, given to Type 2 DM, since you cant make FA, lower VLDL levels
Niacin
in high doses, can raise HDL, by inhibit HSL, reducing FAs coming to liver to make VLDLs
Location of ApoB48 vs B100
intestines vs liver
Binding affinity of ApoB48 and ApoE on CM
ApoE has higher binding affinity in liver, so CM are rapidly taken up by liver (LDL still you E over B100 because of binding affinity)
Different between B48 and B100
B48 lacks LDL-R domain
HDL
highest phospholipid and protein, lowest TG (same as LDL)
CM
lowest phospholipid, cholesterol ester and protein, highest TG
LDL
highest C/CE, same TG as HDL
LPL coactivator?
ApoCII, mutations in either results in high CM, VLDLs
LACT coactivator?
ApoA-1
ABCA1 transporter is for what?
cholesterol efflux from peripheral cells, mutation would lead to increase cholesterol in body tissues and decrease HDL
Foam cells and HDL?
HDL takes cholesterol out of them, reduced sclerotic plaques
