Activation of the Liver X Receptor Increases Neuroactive Steroid Levels


#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 LRXα and β 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 5α-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 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na+, K±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 issues… so an lxr activator could be a big deal…


#3

Interesting find. Didn’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?

I’ll run it by Shippen and Jacobs to get their thoughts if I think of it. Need to set something up with Jacobs but I’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 “remedy” 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-γ ligands. In this study, we show constitutive expression of the nuclear liver X receptor (LXR)α and LXRβ in peripheral human B cells. Activation of LXRs reduced secreted IgE (−68% ± 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% ± 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, −52% ± 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?