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LXR, PPARs, Oxysterols and CYP27A1

In our previous post we discussed about the potential importance of Myosins, TAM Receptors and their connection with Phagocytosis and Endoplasmic Reticulum Stress to the Syndromes discussed in this Blog.  In this post we will hypothesize as to why the LXR Receptor and several other topics (CYP27A1, Oxysterols, PPARGα, PPARγ, LXR) appear in the Network Analysis graph.

You can see how Network Analysis identifies LXR as being important by placing the node close to the center of the Network :




You may also find the Nodes named ppargamma, pparalpha, ,oxysterols and cyp27a1 (CYP27A1 was not previously shown in any Network Analysis) in the diagram below :




According to [1], regarding PPARs and LXR :


"Peroxisome proliferator-activated receptors (PPARs) and (liver X receptors) LXRs are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Because the macrophage plays an important role in host defense and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Research over the last few years has revealed important roles for PPAR-α , PPAR-γ , and LXRs in macrophage inflammation and cholesterol homeostasis with consequences for atherosclerosis development"

According to Wikipedia's entry for Macrophages :


"Macrophages are professional phagocytes and are highly specialized in removal of dying or dead cells and cellular debris. This role is important in chronic inflammation, as the early stages of inflammation are dominated by neutrophils, which are ingested by macrophages if they come of age"


In other words, Macrophages are directly associated with Phagocytosis (potential importance of Phagocytosis was discussed in the previous post) and LXR along with PPARs appear to be an important regulator of Phagocytosis.



In [2] we find several Topics that were also discussed in previous posts :


T-Cells 

"There is evidence for increased cytotoxic T-cell activity in CFS; a recent study suggested that the cytotoxic T-cells are so chronically activated that they have begun to run out of ammunition (perforin)."


ER Stress, UPR, Apoptosis

"Recent evidence indicates that stress in the endoplasmic reticulum (ER) can also induce apoptosis. ER stress may be induced by amyloids (abnormal aggregations of proteins) and the unfolded protein response (UPR)"


Actin


"This suggests that actin, along with RNase L and the other proteins, is being fragmented in the cells of CFS patients. Given actin's immune activities the authors believe that actin fragmentation ‘undoubtedly’ further contributes to the immune problems seen in CFS. G-actin fragmentation could, by taking away the supply of usable actin, negatively impact membrane integrity, phagocytosis, cell adhesion and T-cell activation"


We also find however mentions for Calpain :



"This suggests that calpains are the most immediate source of increased caspase activity in.CFS. So far tests indicate that calpain can fragment RNase L, G-actin, and may be responsible for STAT 1, p53 and RLI fragmentation (!) "

According to Wikipedia about Calpain :



"A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor,  calpastatin."


We note the mention of Calpastatin as being a Calpain inhibitor. Apparently too much Calpain creates several problems :


"Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimer's disease, and cataract formation, as well as secondary degeneration resulting from acute cellular stress following myocardial ischemia, cerebral (neuronal) ischemia, traumatic brain injury and spinal cord injury. Excessive amounts of calpain can be activated due to Ca2+ influx after cerebrovascular accident (during the ischemic cascade) or some types of traumatic brain injury such as diffuse axonal injury. Increase in concentration of calcium in the cell results in calpain activation, which leads to unregulated proteolysis of both target and non-target proteins and consequent irreversible tissue damage. Excessively active calpain breaks down molecules in the cytoskeleton such as spectrin, microtubule subunits, microtubule-associated proteins, and neurofilaments. It may also damage ion channels, other enzymes, cell adhesion molecules, and cell surface receptors. This can lead to degradation of the cytoskeleton and plasma membrane. Calpain may also break down sodium channels that have been damaged due to axonal stretch injury, leading to an influx of sodium into the cell. This, in turn, leads to the neuron's depolarization and the influx of more Ca2+"


However, it appears that LXR increases Calpastatin (which inhibits Calpain) [3] :


"By delivering LXR agonists, T0901317 and GW3965, to mice submitted to 30 minutes intraluminal middle cerebral artery occlusion, we show that LXR activation reduces brain swelling and decreases BBB permeability by upregulating LXR's target calpastatin that deactivates calpain-1/2, stabilizing p120 catenin. p120 catenin specifically interacts with RhoA and Cdc42, inactivating the former and overactivating the latter, thus restoring the postischemic expression, phosphorylation and interaction of the tight junction proteins occludin and zona occludens"

Apparently LXR apart from being relevant to Phagocytosis, it may also be relevant to protection from deleterious results of impaired calcium homeostasis.


We will now try to hypothesise as to why Oxysterols and CYP27A1 appear as central in the Network Graph.

According to Wikipedia :

"Oxysterols are oxidized derivatives of cholesterol, which may be important in many biological processes, including cholesterol homeostasis, atherosclerosis, sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation"

We take note of the association of Oxysterols with Sphingolipid Metabolism, Platelet Aggregation and Apoptosis. Interestingly, Naviaux et al [8] has found impaired Sphingolipid levels in CFS Patients. Interestingly,  LXR activation increases sphingolipid biosynthesis in hepatic cells [9]

Additionaly,  Oxysterols  activate the LXR Receptor and bind and activate Chemokine receptors which belong to the family of the G-Protein Coupled Receptors [5]

Furthermore in [5] we find associations of Oxysterols with :

-B and T Cells


- Specific G Protein-Coupled Receptors. As an example, we read that : "In addition to LXR-dependent mechanisms, oxysterols regulate crucial innate and adaptive immune cell functions through the engagement of GPCRs. For example, the oxysterol 7α,25-OHC can bind and activate the GPCR Epstein–Barr virus-induced 2 (EBI2), which is upregulated on B cells and T cells under specific conditions "

-MERTK, GAS6  (discussed in previous posts) since Oxysterols activate LXRα and LXRβ and both isoforms induce Mertk

Moving forward now to the importance of CYP27A1 and CH25H :


In [6] we read :

"Cholesterol and components of the cholesterol biosynthetic pathway have fundamental roles in all mammalian cells. Hydroxylated forms of cholesterol are now emerging as important regulators of immune function. This involves effects on the cholesterol biosynthetic pathway and cell membrane properties, which can have antiviral and anti-inflammatory influences. In addition, a dihydroxylated form of cholesterol functions as an immune cell guidance cue by engaging the G protein-coupled receptor EBI2, and it is required for mounting adaptive immune responses. In this Review, we summarize the current understanding of the closely related oxysterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, and the growing evidence that they have wide-ranging influences on innate and adaptive immunity."

According to Wikipedia, CYP27A1 is required for the production of Oxysterol 27-HC :

"27-Hydroxycholesterol (27-HC) is an endogenous oxysterol with multiple biological functions, including activity as a selective estrogen receptor modulator (SERM) (a mixed, tissue-specific agonist-antagonist of the estrogen receptor(ER) and as an agonist of the liver X receptor (LXR). It is a metabolite of cholesterol that is produced by the enzyme CYP27A1"

In one of the first posts the importance of Bile Acid metabolism (as suggested by Machine Learning) was discussed. According to [7], CYP27A1 is the rate-limiting enzyme in the alternative bile acid synthetic pathway, and is also responsible for the side chain oxidation in the classic bile acid synthetic pathway.

We therefore see one more example of how Network Analysis -apart from Machine Learning- can be used to generate a hypothesis : In this case we see that Network Analysis selects several Topics that are part of the pathway starting from CYP27A1, the subsequent creation of Oxysterols that activate LXR Receptor through PPARa and PPARg and as a consequence upregulate MERTK and GAS6. Importance of MERTK and GAS6 and its association with ER Stress, Autoimmunity and Phagocytosis were discussed in previous posts.

It should also be stated that Researchers should be probably looking at a combination of Genes rather than just individual Genes. In this case, we hypothesise that impaired functioning on a combination of Genes being discussed could lead to deleterious effects as a result of oxidative stress, autoimmunity, impaired autophagy and ER Stress.

We therefore hypothesise that the following Genes may be of particular interest :

CYP27A1, LXR, PPARa, PPARgamma,CH25H, GPR183, CYP46A1

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