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Immunology Notes > Lipid Signaling > Flashcards

Lipid Signaling Flashcards

1
Q

_____ is a major proinflammatory risk factor

A

Obesity

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2
Q

Instrumentation which made studying lipid immunology possible

A

New-generation liquid chromatography-mass spectrometry

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3
Q

White Adipocytes

A

Contain a single large lipid droplet. Cumulatively can represent ~60% of total body weight.

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4
Q

Adipokines

A

Term for hormones and signaling molecules secreted by adipose tissue. May be protein or lipid in nature.

Includes leptin, estrogen, and proinflammatory cytokines.

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5
Q

Obesity (specifically excessive amounts of white adipocytes) may lead continuous _______, resulting in ________.

A

baseline secretion of pro-inflammatory cytokines, resulting in a chronic low-grade pro-inflammatory state.

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6
Q

Adipose tissue macrophages (ATMs)

A

At the center of adipose tissue-derived inflammation.

May orchestrate secretion of pro- or anti-inflammatory cytokines depending on level of adiposity and phenotype (M1 vs M2).

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7
Q

Lipolysis or short-term low-calorie diets in humans leads to accumulation of ______ in adipose tissue, while obesity/excessive white fat leads to accumulation of _____ in adipose tissue.

A

Lipolysis or short-term low-calorie diets in humans leads to accumulation of M2 anti-infammatory macrophages in adipose tissue, while obesity/excessive white fat leads to accumulation of M1 pro-inflammatory macrophages in adipose tissue.

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8
Q

ATMs produce many immunoactive lipids, including . . .

A

prostaglandins, leukotrienes, and mono- and di-hydroxy unsaturated fatty acids

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9
Q

White adipocytes express many enzymes involved in the synthesis of immunoactive lipids, such as . . .

A

COX-1 and -2, PDG synthase, Thromboxane synthase (for generating prostaglandins and thromboxanes)

5-Lipoxygenase and Leukotriene C4 synthase (for generating leukotrienes and lipoxins)

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10
Q

Classical circulating lipid risk factors for inflammatory disease

A

Cholesteryl esters and low-density lipoprotien.

Particularly effective as risk factors for atherosclerosis and prediction of secondary vascular events.

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11
Q

EPA, DPA, and DPH

A

Omega-3 fatty acids that may be metabolized into pro-resolving lipid mediators, including resolvins and protectins.

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12
Q

Pro-resolving lipid mediators

A

Protectins

Resolvins

Maresins

Lipoxins

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13
Q

Maresin 1 (MaR1)

A

Potent pro-resolving and tissue-regenerating lipid.

Biosynthesized by MΦ, with 12-LOX as an initiating enzyme.

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14
Q

Inhibition of COX-2 _____ resolution.

A

Inhibition of COX-2 delays resolution:

Prostaglandins, despite being pro-inflammatory in most tissues, are also pro-resolution. They are initiators of lipid mediator class-switching.

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15
Q

Aspirin-mediated acetylation of COX-2 . . .

A

blocks the synthesis of prostaglandins by selectively excluding the aracadonic acid metabolite 15R-HETE from the active site. However, the EPA and DPA metabolites 18R-HEPE and 17R-HDHA are not excluded. This blocks proinfammatory PG production while allowing lipoxin, resolvin, and protectin biosynthesis.

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16
Q

Autocoid

A

Locally acting substances that are rapidly biosynthesized in response to specific stimuli, act quickly, and are usually deactivated by metabolism.

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17
Q

COX-1

A

Generally thought of as a homeostatic, housekeeping gene. Adds an epoxide group to arachadonic acid and other lipid metabolites.

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18
Q

COX-2

A

Inducible cyclo-oxygenase with roles in inflammation, pain, fever, pain transduction, mitogenesis, vascular hemodynamics, etc.

May be induced by LPS, TNF-α, IL-1, IL-2, EGF, and IFN-γ. Inhibited by endogenous glucocorticoids, IL-1β, IL-4, IL-10, IL-13, NSAIDs, and other direct COX-2 inhibiting small molecules like Rofecoxib/Viox.

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19
Q

Zileutron

A

Iron chelator which inhibits 5-LOX by cofactor sequestration.

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20
Q

Arachadonic Acid Cascade outline

A
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21
Q

Prostaglandin and Thromboxane Metabolism

A
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22
Q

Leukotriene Metabolism

A
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23
Q

Lipoxin Metabolism

A
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24
Q

Platelet Activating Factor Metabolism

A
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25
Q

Lipid Signaling Overview

A
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26
Q

5-Lipoxygenase

A

Lipoxygenase enzyme which controls production of leukotrienes.

Utilizes iron as a cofactor. Inhibited by Zileutron.

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27
Q

15-Lipoxygenase

A

Controls production of 15-S-HETE, and thereby lipoxins.

Inducible expressed in neutrophils.

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28
Q

Role of cytochrome p450 epoxygenases

A

In cells which do not express cyclooxygenases or lipoxygenases, such as kidney cells, the cytochrome p450 enzymes are the major source of immunoactive lipids (primarily epoxyeicosatrtraenoic acids).

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29
Q

Inactivation of prostaglandins, leukotrienes, thromboxanes, and lipoxins

A

These bioactive lipids are inactivated locally by hydroxylation, beta-oxidation, or omega-oxidation. This renders the lipids hydrophilic, and they are quickly delivered to the kidneys and excreted in urine.

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30
Q

Lipocortins

A

Endogenous inhibitors of phospholipase A2, the enzyme which cleaves arachadonic acid from its membrane phospholipid.

Induced by glucocorticoid signaling, which partially accounts for the immunoinhibitory effects of glucocorticoids.

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31
Q

Annexins

A

Act at GPCRs on leukocytes to block proinflammayory responses and upregulate the receptor for Lipoxin A4.

Expression is induced by glucocorticoids, providing a mechanism for glucocorticoid immunosuppression.

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32
Q

Phospholipase A2 (PLA2)

A

Family of enzymes that hydrolyze phospholipids to release fatty acids, including the precursor for arachadonic acid. Includes three isoforms:

cPLA2: A cytosolic, calcium-dependent isoform.

iPLA2: A calcium-independent isoform.

sPLA2: A secreted form.

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33
Q

How statins interact with pro-inflammatory machinery

A

Statins inhibit HMG-CoA Reductase, which inhibits mutiple lipid biosynthesis pathways including farnesyl and geranylgeranyl isoprenoids which are used in anchors for G-proteins. These include Ras, Rho, and Rac, which have widespread roles in proliferation, inflammation, and apoptosis.

Inhibition of these proteins is an important anti-inflammatory action of statins.

34
Q

Major pathways of eicosanoid formation in inflammation

A

COX

LOX

Cythchrome P450

35
Q

Major product of COX enzymes

A

PGH2

PGH2 is then transformed by various additional enzymes into an active form, which may have a variety of activities.

36
Q

PGH2 Transformation Pathways

A
37
Q

Thromboxane Synthase

A

One of the PGH2 Transformation Enzymes. Acts on COX-1 derived PGH2

Catalyzes the conversion of PGH2 into thromboxane A2.

38
Q

PGF Synthase

A

One of the PGH2 Transformation Enzymes. Acts on COX-1 derived PGH2

Catalyzes the transformation of PGH2 into PGF2α​

39
Q

Cytostolic PGE Synthase

A

One of the PGH2 Transformation Enzymes. Acts on COX-1 derived PGH2

Catalyzes the transformation of PGH2 into PGE2

40
Q

Prostacyclin Synthase

A

One of the PGH2 Transformation Enzymes. Acts on COX-2 derived PGH2

Catalyzes the transformation of PGH2 into PGI2

41
Q

Microsomal PGE Synthase

A

One of the PGH2 Transformation Enzymes. Acts on COX-2 derived PGH2

Catalyzes the transformation of PGH2 into PGE2

42
Q

The Eight Members of the Prostanoid Receptor Family

A

E prostanoid receptors (EP1-4)

D prostanoid receptor (DP1)

F prostanoid receptor (FP)

I prostanoid receptor (IP)

thromboxane receptor (TP)

Splice variants on these also exist.

43
Q

Acidic NSAIDS. . .

A

have been shown to concentrate at inflammatory sites, leading to sustained therapeutic effect.

44
Q

While aspirin is clearly ____, other NSAIDs tend to be _____.

A

While aspirin is clearly cardioprotective, other NSAIDs tend to be predisposing to cardiovascular risk.

This is primarily due to PGI2 blockade in the vasculature.

When given together, COX-1 inhibitors may prevent acetylation of platelet COX-1 by aspirin, reducing aspirin’s cardioprotective effect.

45
Q

Roles of PGE2

A

Mediates pain and edema via interaction with peripheral and central neurons, causing vasodilation.

Signals primarily via EP2, EP3, and EP4, all of which may produce pro- or anti-inflammatory signals depending on which cells are recognizing it and what state they are in.

46
Q

Roles of PGI2

A

Major regulator of vascular tone (promotes vasodilation) and inhibitor of platelet aggregation and white cell rolling. Key mediator of edema. Binding to IP receptors on the spinal cord and DRG triggers a pain response.

47
Q

Roles of PGD2

A

Produced primarily by mast cells, dendritic cells, and Th2s.

Elicits bronchoconstriction and eotaxis. May be further processed into 15d-PGJ2 by other cells, which has anti-inflammatory and pro-resolution activity.

48
Q

Roles of PGF2α

A

Mainly formed via PGF synthase-mediated PGH transformation, but may be generated by conversion from other PGs as well.

-need more info-

49
Q

Role of Thromboxane A2

A

Primarily COX-1 -> Thromboxane synthase derived, but may also be upregualted via COX-2 activation in macrophages.

Stimulates platelet aggregation and adhesion, smooth muscle contraction, and endothelial inflammation.

50
Q

12-LOX is primarily expressed in . . .

A

Platelets

51
Q

5-LOX is primarily expressed in. . .

A

Neutrophils and Mast Cells (granulocytes)

It is cytosolic in its resting state and is mobilized to the nuclear and plasma membranes by calcium release. Differential phosphorylation may modulate its activity.

52
Q

15-LOX is primarily expressed in . . .

A

Alternative Macrophages, Eosinophils, and airway epithelia

Its expression is largely driven by Th2 cytokines.

53
Q

LOX metabolism targets

A

5- and 12-LOX target primarily arachadonic acid, but 15-LOX is more promiscuous, also metabolizing lineolate and other omega-3 fatty acids.

54
Q

LOX-mediated Arachadonate Transformation Pathways

A
55
Q

The primary products of LOX catalysis in cells are ___.

A

The primary products of LOX catalysis in cells are HpETEs.

Which are rapidly reduced by glutathione peroxidases to HETEs.

These may be converted by secondary catalysis into lipoxins, hepoxilins, or leukotrienes

56
Q

LTB4

A

Potent pro-inflammatory leukotriene. Neutrophil chemoattractant that acts via BLT1 and BLT2 receptors.

57
Q

12-LOX, 5-LOX, and 12/15-LOX metabolism pathways

A
58
Q

Hepoxilins

A

Product of 12-HpETE metabolism by e3-LOX or 12/15-LOX

Have a short half-life. Elevate calcium levels in neutrophils

59
Q

Platelet -> endothelial Transcellular metabolism

A

Platelet PGH2 -> Endothelial PGI2

60
Q

Endothelial cell -> platelet Transcellular Metabolism

A

Endothelial PGH2 -> Platelet TXA2

61
Q

Neutrophil -> Endothelium Transcellular Metabolism

A

Neutrophil LTA4 -> Endothelial LTB4 and LTC4

62
Q

EPA and DHA-products

A

Can be metabolized by LOXs to generate pro-resolving lipid mediators of the resolvin, maresin, and lipoxin families.

63
Q

Trouble with measuring bioavailability of EPA and DHA-products

A

No specific antibodies exist, and so there is frequent overestimation of lipid bioavailability.

64
Q

Why is it difficult to translate results of lipid biosynthesis in vitro vs in vivo?

A

Cells can generate higher amounts of lipid mediators in vitro where they are surrounded by exogenous stimuli and nutrients in greater quantities than they see in the body.

In vitro lipid biosynthesis is more a measure of the capacity for biosynthesis than a measure of physiological biosynthesis.

65
Q

The gold standard for systemic eicosanoid concentrations

A

Urine! (Really a “gold” standard)

This is because bleeding may induce an artificial elevation or shift in eicosanoid biosynthesis, making serum unreliable.

66
Q

Best method for unequivocable bioavailability analysis of lipids

A

Chiral chromatography coupled with LC-MS/MS on a urine sample.

67
Q

Endocannabinoids

A

Endogenous esterified forms of arachadonic acid. Include arachidonylethanolimide and 2-arachidonoylglycerol.

These intermediates are then further metabolized to form esterified eicosanoids.

68
Q

Isoprostanes

A

Regioisomers and enantiomers of prostaglandins, generated via non-enzymatic oxidation of arachadonic acid.

Most notable among these is 8-iso-PGF2a

69
Q

8-iso-PGF2a

A

Isoprostane of PGF2a generated by free radicals in states of oxidative stress. Commonly used as a biomarker of oxidative stress.

Elevated in Type 2 diabetes, atherosclserosis, and diabetes.

70
Q

Scramblase

A

Enzyme which catalyzes the movement of phosphatidylethanolamine and phosphatidylserine from the cytoplasmic leaflet (where they inhabit at baseline) to the extracellular leaflet. Activated by calcium mobilization.

This both facilitates clotting by platelets and may act as an “eat me” signal to phagocytes during efferocytosis.

71
Q

Esterified Eicosanoid Generation

A
72
Q

Lysophospholipid Generation Pathway

A
73
Q

Lysophospholipids

A

Generated by phospholipase A1 and A2.

Have been shown to serve as important mediators for intracellular signaling cascades, including lysophosphatidylserine inducing histamine release in mast cells. Signal via GPCRs.

74
Q

Phosphoinositide Metabolism

A
75
Q

PPAR

A

Peroxisome proliferator associated receptors

Family of nuclear receptors that act as transcription factors. There are three isoforms (α, δ, γ) and several splice variants. All PPARs heterodimerize with the retinoid X receptor (RXR) to induce gene expression.

76
Q

PPARγ

A

A major regulator of adipocyte differentiation, insulin sensitivity, adipogenesis, and adipocyte survival.

Many lipids bind to PPARγ with low affinity, but no high-affinity ligand has been identified. It is believed that PPARγ’s role is to sense levels of many related lipids rather than any particular lipid.

Ligand include oxidized lipids, eicosanoids, nitrolipids, polyunsatturated fatty acids, and some prostaglandins.

77
Q

PPARα

A

Displays a similar degree of ligand diversity as PPARγ.

Major sensor of dietary and liver unsatturated fatty acids. Responds rapidly in fasting and starvation. Also displays some function in lipotoxicity and inflammation.

78
Q

PPARδ

A

May induce transcription by a similar mechanism (RXR heterodimerization) as the other PPARs, but is the only PPAR to display transrepression.

Transrepresses Bcl6 to prevent cell proliferation. May act in a pro- or anti- inflammatory manner depending on whether or not it is ligand bound. May interact with PKC in platelets to prevent clotting.

79
Q

Liver X Receptors

A

Exist as α and β isoforms. Similar to PPARs, initiate transcription when bound to RXR. Regulated by cholesterol derivatives, such as oxysterols and desmosterol

80
Q

LXRα

A

Expressed in the liver, intestine, macrophages, and adipose tissue. Regulate genes involved in cholesterol uptake, transport, and excretion.

81
Q

LXRβ

A

More generally expressed in cells across the body than LXRα. Regulate genes involved in cholesterol uptake, transport, and excretion.

Immunology Notes (24 decks)

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