Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Immunology Notes > Lipid Signaling > Flashcards

Lipid Signaling Flashcards

1
Q

_____ is a major proinflammatory risk factor

A

Obesity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Instrumentation which made studying lipid immunology possible

A

New-generation liquid chromatography-mass spectrometry

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

White Adipocytes

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

ATMs produce many immunoactive lipids, including . . .

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

EPA, DPA, and DPH

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Pro-resolving lipid mediators

A

Protectins

Resolvins

Maresins

Lipoxins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Maresin 1 (MaR1)

A

Potent pro-resolving and tissue-regenerating lipid.

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Autocoid

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

COX-1

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Zileutron

A

Iron chelator which inhibits 5-LOX by cofactor sequestration.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Arachadonic Acid Cascade outline

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Prostaglandin and Thromboxane Metabolism

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Leukotriene Metabolism

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Lipoxin Metabolism

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Platelet Activating Factor Metabolism

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Lipid Signaling Overview
26
5-Lipoxygenase
Lipoxygenase enzyme which controls production of leukotrienes. Utilizes iron as a cofactor. Inhibited by Zileutron.
27
15-Lipoxygenase
Controls production of 15-S-HETE, and thereby lipoxins. Inducible expressed in neutrophils.
28
Role of cytochrome p450 epoxygenases
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).
29
Inactivation of prostaglandins, leukotrienes, thromboxanes, and lipoxins
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.
30
Lipocortins
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.
31
Annexins
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.
32
Phospholipase A2 (PLA2)
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.
33
How statins interact with pro-inflammatory machinery
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
Major pathways of eicosanoid formation in inflammation
COX LOX Cythchrome P450
35
Major product of COX enzymes
**PGH2** PGH2 is then transformed by various additional enzymes into an active form, which may have a variety of activities.
36
PGH2 Transformation Pathways
37
Thromboxane Synthase
One of the PGH2 Transformation Enzymes. Acts on COX-1 derived PGH2 Catalyzes the conversion of PGH2 into thromboxane A2.
38
PGF Synthase
One of the PGH2 Transformation Enzymes. Acts on COX-1 derived PGH2 Catalyzes the transformation of PGH2 into PGF2α​
39
Cytostolic PGE Synthase
One of the PGH2 Transformation Enzymes. Acts on COX-1 derived PGH2 Catalyzes the transformation of PGH2 into PGE2
40
Prostacyclin Synthase
One of the PGH2 Transformation Enzymes. Acts on COX-2 derived PGH2 Catalyzes the transformation of PGH2 into PGI2
41
Microsomal PGE Synthase
One of the PGH2 Transformation Enzymes. Acts on COX-2 derived PGH2 Catalyzes the transformation of PGH2 into PGE2
42
The Eight Members of the Prostanoid Receptor Family
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
Acidic NSAIDS. . .
have been shown to concentrate at inflammatory sites, leading to sustained therapeutic effect.
44
While aspirin is clearly \_\_\_\_, other NSAIDs tend to be \_\_\_\_\_.
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
Roles of PGE2
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
Roles of PGI2
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
Roles of PGD2
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
Roles of PGF2α
Mainly formed via PGF synthase-mediated PGH transformation, but may be generated by conversion from other PGs as well. -need more info-
49
Role of Thromboxane A2
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
12-LOX is primarily expressed in . . .
Platelets
51
5-LOX is primarily expressed in. . .
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
15-LOX is primarily expressed in . . .
Alternative Macrophages, Eosinophils, and airway epithelia Its expression is largely driven by Th2 cytokines.
53
LOX metabolism targets
5- and 12-LOX target primarily arachadonic acid, but 15-LOX is more promiscuous, also metabolizing lineolate and other omega-3 fatty acids.
54
LOX-mediated Arachadonate Transformation Pathways
55
The primary products of LOX catalysis in cells are \_\_\_.
The primary products of LOX catalysis in cells are **HpETEs**. Which are rapidly reduced by glutathione peroxidases to **HETE**s. These may be converted by secondary catalysis into **lipoxins, hepoxilins, or leukotrienes**
56
LTB4
Potent pro-inflammatory leukotriene. Neutrophil chemoattractant that acts via BLT1 and BLT2 receptors.
57
12-LOX, 5-LOX, and 12/15-LOX metabolism pathways
58
Hepoxilins
Product of 12-HpETE metabolism by e3-LOX or 12/15-LOX Have a short half-life. Elevate calcium levels in neutrophils
59
Platelet -\> endothelial Transcellular metabolism
Platelet PGH2 -\> Endothelial PGI2
60
Endothelial cell -\> platelet Transcellular Metabolism
Endothelial PGH2 -\> Platelet TXA2
61
Neutrophil -\> Endothelium Transcellular Metabolism
Neutrophil LTA4 -\> Endothelial LTB4 and LTC4
62
EPA and DHA-products
Can be metabolized by LOXs to generate pro-resolving lipid mediators of the resolvin, maresin, and lipoxin families.
63
Trouble with measuring bioavailability of EPA and DHA-products
No specific antibodies exist, and so there is frequent overestimation of lipid bioavailability.
64
Why is it difficult to translate results of lipid biosynthesis *in vitro* vs *in vivo*?
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
The gold standard for systemic eicosanoid concentrations
Urine! (Really a "gold" standard) This is because bleeding may induce an artificial elevation or shift in eicosanoid biosynthesis, making serum unreliable.
66
Best method for unequivocable bioavailability analysis of lipids
Chiral chromatography coupled with LC-MS/MS on a urine sample.
67
Endocannabinoids
Endogenous esterified forms of arachadonic acid. Include arachidonylethanolimide and 2-arachidonoylglycerol. These intermediates are then further metabolized to form esterified eicosanoids.
68
Isoprostanes
Regioisomers and enantiomers of prostaglandins, generated via non-enzymatic oxidation of arachadonic acid. Most notable among these is 8-iso-PGF2a
69
8-iso-PGF2a
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
Scramblase
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
Esterified Eicosanoid Generation
72
Lysophospholipid Generation Pathway
73
Lysophospholipids
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
Phosphoinositide Metabolism
75
PPAR
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
PPARγ
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
PPARα
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
PPARδ
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
Liver X Receptors
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
LXRα
Expressed in the liver, intestine, macrophages, and adipose tissue. Regulate genes involved in cholesterol uptake, transport, and excretion.
81
LXRβ
More generally expressed in cells across the body than LXRα. Regulate genes involved in cholesterol uptake, transport, and excretion.

Immunology Notes (24 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions