Diabetic peripheral neuropathy represents a considerable medical problem in humans especially because the molecular mechanism of this disease is still obscure. This pathology induces neurological complications on both nerve function and structure. Myelin is a biological membrane characterized by high lipid content and it is one of the main structures that contribute to a correct function of the nervous system. The particular characteristics of the lipids present in the myelin sheath provide the electrically insulating property required for the salutatory propagation of the nervous influx. Liver X Receptors (LXRs) belong to nuclear receptors family and they are ligand-activated transcription factors. We previously showed that LXR activation promotes cholesterol utilization to locally increase neuroactive steroid levels in the sciatic nerves to exert neuroprotective effects in diabetic neuropathy. Besides regulating cholesterol homeostasis, LXRs directly activate the expression of the lipogenic transcription factor Sterol Regulatory Element Binding Protein-1c (SREBP-1c), a gene involved in fatty acid synthesis. Recently, is has been highlighted the role of SREBP-1c in the regulation of lipid metabolism during peripheral nerve myelination. Using streptozotocin (STZ)-treated rats, an experimental model of diabetic neuropathy, we observed that LXRs activation by GW3965 (a synthetic LXR ligand) counteracts alterations in myelin caused by diabetes by improving myelin lipid content and restoring the expression levels of major enzymes involved in fatty acid synthesis. We also found that diabetes decreases thermal sensitivity and never conduction velocity in STZ-treated rats, parameters restored at the level of non-diabetic animals by the treatment with the LXR ligand GW3965. These results suggest that LXR activation protects peripheral nerves from neuropathy by modulating cholesterol and lipid metabolism in sciatic nerve of diabetic rats. Supported by a grant from The Giovanni Armenise-Harvard Foundation.

LXR-mediated lipogenesis protects peripheral nerves from type I diabetes-induced myelin alterations / G. Cermenati, E. Brioschi, F. Abbiati, E. Saez, E.S.R. De Fabiani, M. Crestani, L.M. Garcia-Segura, C. Melcangi, D. Caruso, N. Mitro. ((Intervento presentato al convegno EMBO Conference on Nuclear Receptors : from molecular mechanism to health and disease tenutosi a Sitges nel 2011.

LXR-mediated lipogenesis protects peripheral nerves from type I diabetes-induced myelin alterations

G. Cermenati;BRIOSCHI, ELISABETTA;F. Abbiati;E.S.R. De Fabiani;M. Crestani;C. Melcangi;D. Caruso;N. Mitro
2011-09-17

Abstract

Diabetic peripheral neuropathy represents a considerable medical problem in humans especially because the molecular mechanism of this disease is still obscure. This pathology induces neurological complications on both nerve function and structure. Myelin is a biological membrane characterized by high lipid content and it is one of the main structures that contribute to a correct function of the nervous system. The particular characteristics of the lipids present in the myelin sheath provide the electrically insulating property required for the salutatory propagation of the nervous influx. Liver X Receptors (LXRs) belong to nuclear receptors family and they are ligand-activated transcription factors. We previously showed that LXR activation promotes cholesterol utilization to locally increase neuroactive steroid levels in the sciatic nerves to exert neuroprotective effects in diabetic neuropathy. Besides regulating cholesterol homeostasis, LXRs directly activate the expression of the lipogenic transcription factor Sterol Regulatory Element Binding Protein-1c (SREBP-1c), a gene involved in fatty acid synthesis. Recently, is has been highlighted the role of SREBP-1c in the regulation of lipid metabolism during peripheral nerve myelination. Using streptozotocin (STZ)-treated rats, an experimental model of diabetic neuropathy, we observed that LXRs activation by GW3965 (a synthetic LXR ligand) counteracts alterations in myelin caused by diabetes by improving myelin lipid content and restoring the expression levels of major enzymes involved in fatty acid synthesis. We also found that diabetes decreases thermal sensitivity and never conduction velocity in STZ-treated rats, parameters restored at the level of non-diabetic animals by the treatment with the LXR ligand GW3965. These results suggest that LXR activation protects peripheral nerves from neuropathy by modulating cholesterol and lipid metabolism in sciatic nerve of diabetic rats. Supported by a grant from The Giovanni Armenise-Harvard Foundation.
Settore BIO/10 - Biochimica
Settore MED/13 - Endocrinologia
LXR-mediated lipogenesis protects peripheral nerves from type I diabetes-induced myelin alterations / G. Cermenati, E. Brioschi, F. Abbiati, E. Saez, E.S.R. De Fabiani, M. Crestani, L.M. Garcia-Segura, C. Melcangi, D. Caruso, N. Mitro. ((Intervento presentato al convegno EMBO Conference on Nuclear Receptors : from molecular mechanism to health and disease tenutosi a Sitges nel 2011.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/165321
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