37 - Orphan Receptors Flashcards
Do orphan receptors have ligands?
Orphan receptors have no known (or at least generally agreed upon) endogenous ligands
What do orphan receptors bind?
Some of these receptors bind a number of metabolic intermediates such as fatty acids, bile acids, and/or sterols with relatively low affinity
What do orphan receptors function as?
These receptors hence may function as metabolic sensors
Examples of orphan nuclear receptors?
o Bile acid receptor (BAR) or farnesoid X receptor (FXR)
o Liver X receptor
o Peroxisome proliferator-activated receptors (PPARs)
What have been thought to interact with alpha receptors?
Fatty acids are thought to interact with alpha receptors to stimulate transcription
o These being type II receptors for heterodimers with retinoic acid receptors
PPAR are thought to interact with what?
PPAR gamma receptors are thought to interact with prostaglandins so AA gets converted by the action of lipoxygenases and cyclooxygenases, to produce prostaglandins and leukotrienes
o The affinity is very low and prostaglandin G2 is thought to be the best one for interaction with PPAR gamma
o These receptors have been found to serve as important insulin sensitisers, and therefore drugs have been developed to work against them
What are members of the TZD chemical class?
Rosiglitazone and pioglitazone are members of the thiazolidinedione (TZD) chemical class
What do members of the TZD class act as?
They act as full agonists of PPARgamma and thereby induces the transcription and expression of hundreds of genes, some of which enhance insulin sensitivity, thereby underlying its therapeutic effects in type II diabetes
o However, activation of others are thought to lead to side effects of the drugs, including weight gain, fluid retention and oedema, congestive heart failure and bone fracture
Drug treatments for the 2 diabetes
These drugs interact with the PPAR gamma, stimulating transcription
o So we have co-repressors switching for co-activators and some od the target genes including a hormone called leptin which is involved in appetite, TNF alpha and protein involved in fat metabolism
o Through these interactions with the PPAR receptor, the orphan receptor, the TZDs act on fat cells, muscle cells and liver cells
What about bone microarchitecture?
o Increased adipogenesis and decreased osteogenesis
o It was recently found that TZDs increase the risk of bone fracture in patients with type II diabetes
- This is caused by the TZDs increased fat production and decreased bone production
o Weakening of the bone in exchange for increased fat production
What stem cells are derived from the same thing?
The stem cells that synthesise the fat cells in bone marrow and the cells that stimulate bone formation, osteoblasts, derive from the same stem cells in the bone marrow
o So if we have the same stem cells that can produce osteoblasts that is switched to make fat cells, there is no longer production of osteoblasts
- Switch off of bone mineralisation in favour of fat cell development
o There are also chondrocytes which can switch off osteoblast production
What do pluripotent MSCs differentiate into?
Pluripotent MSCs differentiate into osteoblasts, which can synthesise bone
o This required the coordinated action of transcription factors starting with Runx2 which drive the differentiation towards the mature osteoblasts
What are mature osteoblasts characterised by?
The mature osteoblasts are characterised by expressing proteins called osteocalcin and osteopontin
What is there in the middle stage?
In the middle stage there is expression of alkaline phosphatases, which is a marker for the early stages of osteoblast differentiation, but central to this is activation of Runx transcription factor which activates the target genes responsible for converting the cells to osteoblasts
A different pathway is required for the conversion of stem cells to fat cells
In this case we have the action for a different class of transcription factors
- First we have CEBPs and PPARgamma which drives differentiation of stem cells through to preadipocyte stages
- They express lipids and fill up with fat so they express fatty acid binding proteins
- But the early stages we have activation of PPAR which drives the osteoprogenitor cells to the preadipocyte stage and then final differentiation
