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144 Cards in this Set
- Front
- Back
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why is the transport of mitochondrial acetyl-CoA important to FA synthesis?
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transport of acetyl-CoA is coupled with transport of citrate, which is an allosteric inhibitor of PFK1 (slows down glycolysis since cell is in energy-rich state)
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what are the two requirements for FA synthesis to occur?
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substrate availability
high ATP/ADP |
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what enzyme couples transport of mitochondrial acetyl-CoA with NADPH synthesis?
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malic enzyme
(catalyzes decarboxylation of malate to pyruvate) |
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what is epigenetics?
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phenotype manifest due to something on someone's DNA rather than something encoded by their DNA
(e.g. methylation, histone modifications) |
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what enzyme's activity is essential for increased histone acetylation?
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ATP-citrate lyase
(cleaves acetyl-CoA from citrate) |
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where is ATP-citrate lyase found?
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cytoplasm
nucleus (same reaction in both) |
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how is overall gene expression affected by citrate concentration?
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acetylation of histones via acetyl-CoA increases transcription by causing DNA to unwind
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what is the activation step in FA synthesis?
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carboxylation of acetyl-CoA by acetyl-CoA carboxylase
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what is ACC?
what does it do? |
Acetyl-CoA carboxylase
carboxylates acetyl-CoA to malonyl-CoA using bicarbonate ion |
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in what tissues is ACC1 enriched?
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liver
adipose lactating mammary tissue |
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where in the cell is ACC1 located?
where in the cell is ACC2 located? |
cytosol
mitochondrial matrix |
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in what tissues is ACC2 found?
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liver
skeletal muscle |
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why does ACC2 co-localize with CPT-1?
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this allows efficient regulation of CPT-1 through malonyl-CoA
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what two molecules must be present to make fatty acids?
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acetyl-CoA
malonyl-CoA |
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what is FAS?
what does it do? |
Fatty Acid Synthase
carries out the reactions required to make fatty acids head-to-tail homodimerization |
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what are the two portions of FAS?
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synthetase portion
Acyl Carrier Protein (ACP) portion |
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what is the process of reactions in FA synthesis?
what is the process of reactions in FA oxidation? |
reduction, dehydration, reduction
oxidation, hydration, oxidation |
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what allows an elongating fatty acid to swing around on FAS?
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B5 on acyl carrier protein
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what is the rate-limiting step in FA synthesis?
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acetyl-CoA carboxylase
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what is the major negative regulator of ACC?
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AMPK
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what is the allosteric activator of ACC which induces its polymerization (ACC1 particularly)?
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citrate
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which fatty acids inhibit ACC?
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mostly long chain, but short chains can also
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what hormone stimulate the de-phosphorylation of AMPK sites on ACC?
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insulin
(when ACC is phosphorylated, it is less active so FA synthesis is slow) |
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what enzyme phosphorylates AMPK to activate it?
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AMPKK
aka PJS aka STK11 (serine-threonine kinase 11) |
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what enzyme also phosphorylates ACC, though less important than AMPK?
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PKA
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what hormone stimulates phosphorylation and inhibition of ACC?
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glucagon
(epinephrine) |
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what is the effect on FA synthesis of PKA phosphorylating PPI-1?
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PPI-1 is activated, which allows it to phosphorylate PP-1
when phosphorylated, PP-1 is less active, so phosphate removal from ACC is inefficient this causes inhibition of FA synthesis |
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what type of diet leads to increased FA synthesis?
decreased FA synthesis? |
+ - high carb, fat-free
- - high fat (also fasting and glucagon) |
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what two transcription factors affect regulate the transcription of FA synthesis genes?
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SREBP
ChREBP |
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what is the allosteric activator of FAS?
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phosphorylated sugars (mostly G6P)
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how does activation of AMPK affect FAS levels?
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leads to decreased expression, via SREBP
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what effect does glucose uptake have on FAS levels?
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leads to increased expression, via ChREBP
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what is the master lipid regulator in the liver?
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ChREBP
(induced in liver when glucose rises) |
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what inhibits the transcriptional activity of ChREBP?
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phosphorylation by PKA and/or AMPK
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what activates the transcriptional activity of ChREBP?
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dephosphorylation by PP2Adelta
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what molecule activates PP2Adelta?
where does it come from? |
xylulose-5-phosphate
from pentose phosphate pathway |
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what are the sites bound by ChREBP?
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carbohydrate response elements
(ChoREs) |
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what are the target enzymes for ChREBP?
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L-PK
ACC FAS |
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what proteins are bound by glucose to activate ChREBP expression?
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Liver X Receptors (LXR)
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what protein is responsible for controlling 50% of overall hepatic lipogenesis?
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ChREBP
(through concerted action on glycolytic and lipogenic genes) |
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where does elongation of FAs occur?
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membranes of ER
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what enzymes introduce sites of unsaturation?
what positions? |
fatty acyl-CoA desaturases
positions 5, 6, and 9 |
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what two fatty acids are essential?
why? |
linoleic acid
linolenic acid because they have unsaturations beyond position 9 |
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what is the rate-limiting enzyme of MUFAs?
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microsomal delta-9-stearoyl-CoA desaturase (SCD)
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what are the major MUFAs in membrane phospholipids, cholesterol, and TAGs?
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oleic acid
palmitoleic acid |
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what are the three important omega-3 fatty acids?
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alpha linolenic acid (ALA)
eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA) |
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what is the important omega-6 fatty acid?
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arachidonic acid (AA)
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why is ALA important as a fatty acid?
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it is a precursor for EPA and DHA
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what inhibits the ability of the body to convert ALA to EPA and DHA?
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delta-6 and especially delta-5 desaturases are naturally inefficient enzymes, however they are feedback inhibited by EPA which brings their activity to nearly a stand-still
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what is the optimal ratio of consumption for omega-6:omega-3 FAs? what is common in western diet?
what is the optimal ratio of consumption for EPA:DHA? |
2:1
100:1 2:1 |
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what types of anti-inflammatory lipids are derived from EPA and DHA?
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resolvins (Rvs)
Protectins (PD) |
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what effect do E series resolvins have on the inflammatory cycle?
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reduce inflammation
regulate PMN transendothelial migration reduce dendritic cell function regulate IL-12 production |
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derivation from what tissue gives PD1 its alternative name? what is its function in that tissue?
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neural tissues (aka NPD1)
has protective role in ischemia-reperfusion injury |
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what omega-3 FA is essential for proper development of prenatal and postnatal CNS?
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DHA
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which omega-3 FA has beneficial effects on behavior and mood?
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EPA
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what algae has EPA and DHA in it (humans can consume it to get EPA and DHA)?
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spirolena
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what transcription factor (family) do omega-3 FAs bind to directly? what effect does this have?
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PPARalpha
activate the fatty acid oxidation (in peroxisomes) in the liver |
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what is the primary function of peroxisomes?
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synthesis and degradation of long chain fatty acids
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how do omega-3 fatty acids inhibit hepatic fatty acid synthesis?
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suppress SREBP in three ways:
inhibit gene expression enhance degradation of mRNA (encoding SREBP) increase proteosomal degradation of SREBP |
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what are the targets of SREBP?
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FAS
ACC |
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how are EPA and DHA packaged in cold water fish? krill?
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TAGs
Phospholipids |
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why are phospholipids better sources of EPA and DHA than are TAGs?
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because there is no specificity in the FAs attached to each position, there is small probability EPA and DHA will be on a cleaved position (Sn2) and will therefore be absorbed
in phospholipids, the Sn2 position contains mostly unsaturated FA (almost at 100%) and will be cleaved by PLA2 - the lysophospholipid and FFA are absorbed and repackaged |
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what is the effect of having too many VLDLs in the blood?
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coronary artery disease
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what are the three subtypes of glycerolipids (lipids based on glycerol backbone)?
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triacylglycerols
glycerophospholipids ether glycerolipids |
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what are the three subtypes of phospholipids?
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glycerophospholipids
ether glycerolipids sphingophosppholipids |
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what are the two subtypes of sphingolipids?
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sphingophospholipids
glycolipids |
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what are glycerophospholipids?
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phosphatidylcholine
phosphatidylserine phosphatidylethanolamine phosphatidylinositol bisphosphate phosphatidylglycerol cardiolipin |
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what are the ether glycerolipids?
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plasmalogens
platelet activating factor |
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what is the only type of sphingophospholipid?
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sphingomyelin
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what are the glycolipids?
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cerebrosides
sulfatides globosides gangliosides |
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what causes Tay-Sachs?
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inability to degrade sphingomyelin
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what enzyme in the biosynthetic pathway of TAGs is also a transcription factor?
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Phosphatidic Acid Phosphatase
aka PAP1 aka Lipin-1 |
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what is the important entry point for de novo FA synthesis?
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glycerol-3-phosphate acyltransferase
aka GPAT |
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what important role does phosphatidic acid have? how does it get to its final product?
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converted to glycerophospholipids
can get to different glycerophospholipids through two different paths, but both require a nucleotide-activated intermediate |
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what causes Majeed syndrome?
what are the symptoms? |
defect in Lipin-2 gene
cutaneous inflammation and recurrent fevers |
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what are the roles of PAP1?
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remove phosphate from diacylphosphatidic acid
co-activates transcription of beta-oxidation genes |
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what type of cell requires PAP1 to mature?
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adipocytes
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what two transcription factors does PAP1 interact with?
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PPARgamma coactivator 1alpha
PPARalpha |
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what enzymes are targets of PAP1?
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carnitine palmitoyl transferase-1
acyl-CoA oxidase medium-chain acyl-CoA dehydrogenase |
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what type of drugs exert their action via lipin-1?
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Thiazolidinedione (TZD)
a type of diabetes drug |
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what are the two ways membrane composition of phospholipids can be changed?
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de novo synthesis of phospholipids
interchange between different phospholipids |
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what is the primary molecule that exacerbates inflammatory response to antigens?
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platelet activating factor
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what are the functions of platelet activating factor?
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increase vasopermeability
increase vasodilation increase bronchoconstriction functions in hypersensitivity, acute inflammatory reactions, and anaphylactic shock |
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what position of phospholipid or triglyceride does PLA2 cleave at?
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Sn2
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what position of phospholipid does PLC cleave at?
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Sn3, removing head group and all
ex: PLCgamma |
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what is the building block of sphingolipids?
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sphingosine
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what is ceramide?
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N-acetylated sphingosine
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what is sphingomyelin composed of?
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Ceramide and phosphatidylcholine
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what is galactocerebroside composed of?
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ceramide with one galactose
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what is a sulfatide composed of?
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ceramide with one sugar and a sulfate
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what is a globoside composed of?
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ceramide with several sugars
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what is the only cerebroside (ceramide with a single sugar) that is naturally occuring in blood serum?
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galactocerebroside
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what is a ganglioside composed of?
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ceramide, several sugars, and at least one sialic acid (N-acetylneuracytic acid or NANA)
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what are eicosanoids?
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biologically important lipids derived from 20-C FAs
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which eicosanoids undergo the cyclic pathway for synthesis?
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both prostaglandins and thromboxains contain cyclic structure and therefore undergo the cyclic pathway for synthesis
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which eicosanoids undergo the linear pathway for synthesis?
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leukotrienes have no cyclic structure and therefore undergo the linear pathway for synthesis
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what are the precursor fatty acids for arachidonic acid?
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linoleic acid and linolenic acid
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which precursor molecules for arachidonic acid are also anti-inflammatory precursors?
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gamma-linolenoyl-CoA
dihomo-gamma-linolenoyl-CoA (GLA and DGLA) |
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how does DGLA have anti-inflammatory capabilities?
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precursor for series 1 eicosanoids which work against major series 2 cyclic eicosanoid counterparts
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when can compromise the already slow activity of delta-6-desaturase?
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nutritional deficiency
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what is the effect of delta-5-desaturase activity being low?
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most DGLA formed from GLA doesn't proceed to arachidonic acid, so it is inserted into membrane phospholipids at the same location as AA
this DGLA can then compete with AA to be released/activated by PLA2 |
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what is the first step (after the release of AA from phospholipids) in the cyclic lipid pathway?
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conversion of AA to PGG2 by cyclooxygenase
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what is COX?
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cyclooxygenase (1 and 2)
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which COX enzyme is inducible in inflammatory cells?
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COX2
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what enzyme catalyzes the conversion of PGH2 to prostacyclin (PGI2)
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prostacyclin synthase
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what is the first step (after cleavage of arachidonic acid from phospholipids) of the linear lipid pathway?
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conversion of AA to LTA4, via 5-HPETE and 5HETE, using 5-lipoxygenase (5-LOX)
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what is the peptidoleukotriene pathway?
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the pathway by which leukotrienes (except LTB4) are formed from LTA4
LTA4 -> LTC4 -> LTD4 -> LTE4 -> LTF4 |
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what is the primary pathway for leukotriene synthesis in neutrophils?
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LTB4 from LTA4, via LTA4 hydrolase
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what enzyme does aspirin inhibit? how?
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COX-2 (AA cannot be converted to PGG2, or any subsequent cyclic lipids)
suicide inhibition, by permanently binding to the enzyme |
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why is aspirin's effect on PGI2 less than its effect on TXA2?
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prostacyclin is produced in healthy endothelial cells to inhibit platelet aggregation, whereas TXA2 is produced in platelets to stimulate platelet aggregation
since platelets cannot build new enzymes, and aspirin suicide inhibits the COX-2 enzymes present, new platelets must be synthesized in order to produce TXA2 again, whereas affected endothelial cells can just make new COX-2 |
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what are the two most important cyclic lipids inhibited by aspirin's action?
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PGI2 - inhibits platelet aggregation, induces vasodilation
TXA2 - induces platelet aggregation, induces vasoconstriction |
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what are the functions of PGE2?
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potent vasodilator
enhances effects of bradykinin and histamine induces uterine contractions induces platelet aggregation |
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what are the functions of PGF2?
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vasoconstriction
induces smooth muscle cell contraction |
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what are the functions of PGI2?
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inhibits platelet aggregation
induces vasodilation |
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what are the functions of TXA2?
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induces platelet aggregation
induces vasoconstriction |
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what are the functions of TXB2?
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induces vasoconstriction
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what are the functions of LTB4?
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induces leukocyte chemotaxis and aggregation
(LTB4 is the most important pro-inflammatory molecule) |
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what are the functions of LTC4, LTD4, and LTE4 aka slow reactive substance of anaphylaxis?
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induce slow protracted smooth muscle cell contraction
increase vascular permeability attract and activate leukocytes |
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what are the GPCRs for PGD, PGE, and PGI2 coupled with?
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PGD and PGI2 couple to cAMP
PGE couples to PLCgamma |
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What do LT receptors act through?
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GPCRs as well as PPARs
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which LT binds to BLT1 and BLT2?
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LTB4
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what are TX receptors coupled to?
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PLCgamma via a GPCR
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what is the product of COX action on DGLA?
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series 1 prostaglandins and thromboxanes
(PGE1 and TXA1) |
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what is the product of 15-LOX action on DGLA?
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15-HETrE
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how does 15-HETrE exhibit an anti-inflammatory effect?
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inhibits 5-LOX, so that arachidonic acid cannot be converted to LTB4
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how is aprostadil used to treat ductal-dependent congenital heart disease in newborns?
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it maintains a patent ductus arteriosus until surgery can be performed to correct the problem
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in endothelial cells and monocytes, when acetylated by aspirin, what effect does COX-2 have on AA?
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converts it to 15R-HETE
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what is the product of 15R-HETE in leukocytes?
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via 5-LOX, leukocytes convert 15R-HETE into 15-epi-LXA4 and 15-epi-LXB4
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what is the product of 15-LOX action on AA? where does this occur?
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15S-H(p)ETE
occurs in airway epithelia |
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what happens to 15S-H(p)ETE when it interacts with 5-LOX? where does this occur?
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conversion to 15S-epoxytetraene and then LXA4
occurs in leukocytes |
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what is the product of AA when it interacts with 5-LOX? where does this occur?
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LTA4
occurs in leukocytes |
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what happens to LTA4 from leukocytes when it enters platelets?
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it interacts with 12-LOX to form LXA4
(also forms LXB4, though not with 12-LOX) |
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what is the GPCR that binds lipoxins?
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ALXR
(a member of the formyl peptide receptor family) |
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what are the functions of lipoxins?
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reduce PMN and neutrophil infiltration
stimulate non-phlogistic uptake of apoptotic PMNs by macrophages block IL-8 gene expression block TNF-alpha release and action stimulate TGF-beta regulate actions of histamine |
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what vasodilators do LXA4 molecules induce?
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PGI2 and NO
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what is a unique quality about aspirin as a non-steroidal anti-inflammatory drug?
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only NSAID to induce NO
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what enzymes generate the lipoxin epimers from 15R-HETE?
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LX synthases
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what is the main function of NO?
|
relax smooth muscle
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How is RvE1 produced?
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acetylated COX-2 (via action of aspirin) converts EPA to 18R-HEPE, which is transferred to neutrophils where it is acted on by 5-LOX to yield RvE1
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what receptor does RvE1 bind to?
what effect does this have on adherent nucleophils? dendritic cells? PBMCs? |
BLT1 (aka Chem23) which is only expressed when cells are active
neutrophil - reduces infiltration dendritic cells - reduces IL-12 production and migration PBMCs - increases activation & apoptotic PMN phagocytosis |
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what is a PBMC?
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peripheral blood mononuclear cell
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what omega-3 FA is the primary precursor for protectins?
what enzyme converts this FA to protectins? |
DHA
15-LOX |
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what are the mechanisms by which protectins reduce inflammation?
|
reduces PMN infiltration
dampens NFkappaB expression dampens COX-2 induction |
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which version of the COX enxyme is ubiquitously expressed?
which is only expressed in pro-inflammatory response of inflammatory cells? |
COX-1 is ubiquitously expressed
COX-2 is selectively expressed |
