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. 2010 Sep 8;30(36):11896-901.
doi: 10.1523/JNEUROSCI.1898-10.2010.

Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy

Gaia Cermenati  1 , Silvia Giatti, Guido Cavaletti, Roberto Bianchi, Omar Maschi, Marzia Pesaresi, Federico Abbiati, Alessandro Volonterio, Enrique Saez, Donatella Caruso, Roberto Cosimo Melcangi, Nico Mitro
Affiliations

Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy

Gaia Cermenati et al. J Neurosci. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
A, LXRα and LXRβ are expressed in sciatic nerve and their levels are unchanged between control and STZ-treated rats. B, LXR activation by GW3965 treatment induces mRNA levels of ABCA1 and ABCG1, classical LXR target genes involved in cholesterol efflux in the sciatic nerve. These data indicate that the ligand reaches the sciatic nerve and that the LXRs are activated. C, Expression levels of HMGCoA reductase and SREBP-2, two genes involved in cholesterol synthesis. The mRNA levels of these genes are unchanged by diabetes and/or by GW3965 treatment. The bars represent the relative mRNA expression of shown genes to the housekeeping gene 36B4. Data are presented as mean ± SEM (n = 9). Statistical analysis is performed by one-way ANOVA followed by Tukey–Kramer posttest. *p < 0.05, **p < 0.001 vs control rats; #p < 0.05, ##p < 0.001 vs STZ-treated rats.
Figure 2.
Figure 2.
Gene expression of steroidogenic acute regulatory protein (StAR), translocator protein-18 kDa (TSPO), cytochrome P450 side chain cleavage (P450scc) and 5α-reductase (5α-R), in sciatic nerve. As shown, LXR activation by GW3965 treatment in diabetic rats restores to normal levels the expression of StAR, P450scc and 5α-R but it does not affect TSPO levels. The bars represent the relative mRNA expression of shown genes to the housekeeping gene 36B4. Data are presented as mean ± SEM (n = 9). Statistical analysis is performed by one-way ANOVA followed by Tukey–Kramer posttest. *p < 0.05, **p < 0.001 vs control rats; #p < 0.05, ##p < 0.001 vs STZ-treated rats.
Figure 3.
Figure 3.
Thermal sensitivity, nerve conduction velocity, and Na+, K+-ATPase activity in control, STZ and STZ treated with GW3965 rats. Data are expressed as withdrawal latency in seconds for heat sensitivity threshold (control, n = 10, STZ, n = 12; STZ + GW3965, n = 14), as m/s for NCV (control, n = 14; STZ, n = 12; STZ + GW3965, n = 14) and as μmol Pi/h per mg protein for Na+, K+-ATPase (control, n = 6; STZ n = 7; STZ + GW3965, n = 6), and are mean ± SEM. Statistical analysis is performed by one-way ANOVA followed by Tukey–Kramer posttest. *p < 0.05, **p < 0.001 vs control rats; #p < 0.05, ##p < 0.001 vs STZ-treated rats.
Figure 4.
Figure 4.
Gene expression of myelin proteins in sciatic nerve. The bars represent the relative mRNA expression of shown genes to the housekeeping gene 36B4. Data are presented as mean ± SEM (n = 9). Statistical analysis is performed by one-way ANOVA followed by Tukey–Kramer posttest. *p < 0.05, **p < 0.001 vs control rats.
Figure 5.
Figure 5.
Proposed model of LXRs activation in diabetic neuropathy. The entrance of cholesterol into mitochondria is accomplished by the steroidogenic acute regulatory protein (StAR), a transport protein that regulates cholesterol transfer from the outer mitochondrial membrane to the inner membrane. Here, cholesterol is the substrate of P450scc enzyme, the first enzymatic step in the neuroactive steroid synthesis. A, In the diabetic state, we observed a reduced neuroactive steroid synthesis in the sciatic nerve due to decreased expression of StAR, P450scc and 5α-reductase (5α-R). B, The treatment of diabetic rats with the GW3965, a LXR synthetic ligand, restored the expression of the steroidogenic enzymes, and the neuroactive steroid levels affected by diabetic neuropathy. Moreover, LXR activation also induced the expression of the cholesterol efflux genes such as ABCA1 and ABCG1. In conclusion, the activation of LXRs promotes cholesterol utilization and finally protects from peripheral neuropathy-induced diabetes.
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