Activation of the Liver X Receptor Increases Neuroactive Steroid Levels

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#1

jneurosci.org/content/30/36/11896

Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXĪ± and Ī² isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5Ī±-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3Ī±-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na+, KĀ±ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.

#2

btw irwig says neuroactive steroids could be what is causing our issuesā€¦ so an lxr activator could be a big dealā€¦

#3

Interesting find. Didnā€™t Goldstein just start a study looking into neuroactive steriods? Sorry, some of that paper is a bit above me. Would this be easy to test and anyone have any idea if a treatment would be available?

Iā€™ll run it by Shippen and Jacobs to get their thoughts if I think of it. Need to set something up with Jacobs but Iā€™ll be seeing Shippen next month.

#4

i doubt it would be easy to test, but as the paper states:

These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.

though we are not diabetic, i know many of us are experience variable neuropathy, and are undoubtedly suffering from some level of reduced neurosteroids - as irwig hypothesizes.

#5

very interesting golf. I think neuropathy is associated with e.g. penile insensitivity. Many of us suffer from insensitivity etc.
Unfortunately, I think it takes years (if not a decade or more) until a ā€œremedyā€ is on the market.

#6

Funnily enough golf i was just reading about the LxR. And considering a few of us have high IgE

B lymphocytes play a fundamental role in the development of IgE-dependent allergic immune reactions. Upon appropriate activation, IgE class switch recombination is initiated in B cells, followed by terminal differentiation to IgE-secreting plasmablasts. This process is controlled by different nuclear receptors, including receptors for vitamin D, retinoids, and peroxisome proliferator-activated receptor-Ī³ ligands. In this study, we show constitutive expression of the nuclear liver X receptor (LXR)Ī± and LXRĪ² in peripheral human B cells. Activation of LXRs reduced secreted IgE (āˆ’68% Ā± 11) in CD40 and IL-4 activated B cells. The production of other isotypes, including IgG, IgM, IgA and B cell homeostatic parameters were not significantly altered by LXR activation. We identified inhibitory action of LXR activation on IgE production involving reduced phosphorylation of JNK and increased membrane CD23 expression (38% Ā± 11). The biological significance of our findings was validated by showing that systemic treatment of type I-sensitized BALB/c mice with LXR ligands reduced the serum concentrations of Ag-specific IgE in a dose-dependent manner (maximum, āˆ’52% Ā± 14). Thus, our data indicates that LXRs are involved in the control of IgE secretion by differentiating B cells.

#7

Just came across this thread, this could have some serious impact on us. Has anyone ever tried an LXR Activator? It seems to have potent effects on 5a-reductace and neurosteroid levels.

How would one get a hold of an LXR activator?

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#8

I just saw this post now and happened to notice that it was posted in 2011ā€¦! I find this post also extremely interesting as the methodology i use also identified LXR Receptor as important. Here is a snapshot from a Network Analysis output:

Also of interest is that the thread contains mentions on ABCA1 and ABCG1. Again, spot on @golf !

Here is a snapshot from the presentation i gave regarding Chronic fatigue syndrome in London on Sept 2018, slide 44:

LXR
LXR1499Ɨ1114 77.7 KB

Activation of LXR can happen through many ways.

#9

So what kind of things can we do or take right now to test this

#10

@Lostinaustin i am not sure if i can give any kind of this advice here because it may be considered as medical advice

#11

Wonā€™t consider itmedical advice. We want your opinion as a non medical person. Liver cleanse? What can we do in your opinion? Obviously we will all research before doing anything and make our own decisions

#12

@mariovitali Hey, it looks like your Network Analysis output has a bunch of the wording blurred out.

#13

Here is another version:

Note that CYP27A1, CYP7B1 have been selected which are involved with Bile acids metabolism.

And here is a snapshot from a blog post i made regarding LXR and ABCA1 (among others):

#14

Research suggests that LXR activation can be achieved with Jiaogulan:

Abstract

Liver X receptors (LXR) play an important role in cholesterol homeostasis by serving as regulatory sensors of cholesterol levels in tissues. The present study reports a novel LXR-alpha activator, (20S)-2alpha, 3beta, 12beta, 24(S)-pentahydroxydammar-25-ene 20-O-beta-d-glucopyranoside (TR1), a dammarane-type gynosaponin, isolated from the herbal medicine, Gynostemma pentaphyllum. Gynosaponin TR1 demonstrated greater selectivity toward activation of the LXR-alpha isoform than LXR-beta in HEK293 cells. TR1 selectively enhanced LXR-mediated transcriptional activation and protein expression of ABCA1 and apoE gene expression and secretion in THP-1-derived macrophages. The selectivity of TR1 for LXR-alpha was consistent with ligand docking studies, which showed favourable interaction of TR1 in the LXR-alpha-binding domain, whereas the presence of the sugar substituent interfered with binding to the LXR-beta site. Findings from the present study may provide insight into the development of pharmaceutical agents for treating atherosclerosis.

However it is not that easy because i believe that a personalised approach is needed. I will post more soon.

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#15

I think activating PXR will also temporarily relieve symptoms, partially due to fixing a Th1/Th2 imbalance. Things that can achieve this would be blue cheese or other moldy food.