EXAM Lecture 19 Flashcards
Lipid rafts and signal transduction
cell signal transduction cascades require efficient protein-protein interactions:
- ligand binds to receptor on cell surface
- membrane associated proteins recruited to receptor and associate at inner leaflet of plasma membrane
- protein protein interactions can happen leading to activation of a transcription factor
LIPID RAFTS can bring the plasma mebrane protein (receptor) and membrane associated proteins together
some proteins are localized (wtihin) raft in plasma membrane
- if you disrupt the raft, you disrupt the whole cascade
- if the proteins get displaced from raft, cascade interrupted
some proteins are NOT localized to lipid rafts; cell signal transduction cascades are NOT impacted by raft
non raft region of plasma membrane called bulk membrane
DHA and lipid rafts
lipid rafts are enriched in cholesterol and transmembrane/membrane associated protein
DHA has a high degree of unsaturation, is sterically incompatible with cholesterol (its bulky just like cholesterol due to 6 double bonds)
- disrupts lipid rafts and increases their size (makes proteins less close together), leads to less efficient protein-protein interactions
- DHA has benefits but we don’t want this
by increasing size of lipid rafts, DHA will either
- make the transmembrane and peripheral lipid raft proteins physically further apart
- push the protein out of the raft completely
Signalling pathways that rely on lipid rafts for efficient signalling
IBD
- T cell activation
- Th17 requires IL-6 signalling through IL-6 receptor for activation; IL-6R localizes to lipid rafts
Obesity
- TLR2/4
- leptin receptor
- TNFa and IL6 receptor
disruption of lipid rafts (by DHA etc) will reduce activation of NFkB and STAT3 and reduce inflammatory mediator production
IBD clinical features
excessive inflammation in colon
- immune cell infiltration, goblet cell depletion, destruction of crypts (stem cells)
- overall tissue damage and loss of epithelial membrane
- crypt distortions can turn into ACFs (tumor precursor)
two conditions:
- ulcerative colitis (UC)
- chrons disease (CD)
there is no therapy for maintaining remission
complex multifactorial disease
- activation of adaptive (Th17) and regulatory (Tregs) arms of the intestinal immune system
UC = ulcers only
CD = ulcers and/or polyps
- polyps are ulcers that tried to heal
- they increase cancer risk
regional differences in types of IBD
- dependent on which part of GI tract is affected
IBD complications
- resistant to drug therapy (immunomodulators like anti TNFa)
- perforation of bowel wall
-increased risk of colorectal cancer
-colon surgical removal - treatment intervention
once in remission, need to rebuild colon architecture
aim of dietary inteventions:
- delay relapse or extend remission AND reduce severity of relapse
Cell types involved in IBD inflammatory process
end result:
chemokine production
- recruit more immune cells into inflamed colon
inflammatory cytokine production
- activate other cell types to cause tissue damage
reactive oxygen species
- cause cellular AND DNA damage
- can lead to ACF formation
Extra intestinal complications of IBD
joint inflammation
eye inflammation
ankylosing spondilitis
primary schelorsing cholangitis (PSC)
osteoporosis
skin conditions, mouth sores, blood clots
IBD diagnosis and fecal monitoring
endoscopic is the norm but its invasive and espensive, doesnt discriminate between IBD and IBS
alternatives:
- fecal calprotectin
- fecal immunochemical test (FIT)
- fecal lactoferrin
- fecal metalloproteinases (MMPs)
- fecal myeloperoxidase (MPO)
Microbial dysbiosis in IBD
significant changes in IBD patients mucoal biopsies at the PHYLUM LEVEL:
- reduced frimicutes and bacteroidetes
- increase in less abundant phylas like proteobacteria and sacchari bacteria
- increased colonic inflammation is associated with decreased taxa richness
