Diabetic peripheral neuropathy (DPN) is associate with damages and abnormalities in myelin sheath. Similar changes have been observed in the peripheral nerves of streptozotocin (STZ)-treated rats, a model of type 1 diabetes. It is well known that diabetes blunt levels of neuroprotective molecules such as neuroactive steroids and we observed that the pathology induces a different lipid pattern in myelin due to an altered balance between saturated and unsaturated fatty acids, reduces cholesterol levels in myelin sheath and modifies expression of several important genes involved in lipid metabolism such as sterol regulatory element binding protein 1c (SREBP-1c). Liver X Receptor (LXR) is a ligand-activated nuclear receptor that controls cholesterol and lipid metabolism directly regulating the expression of several genes involved in these pathways. In fact LXR family regulates adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that also in sciatic nerve of rat both LRXα and β isoforms are expressed and that these receptors are functional. We observed that activation of LXRs in rat, using a synthetic ligand, is able to increase most of the enzymes involved in steroidogenesis rising neurosteroids levels and triggering protective effect of the sciatic nerve against DPN ameliorating physiological and functional tests. Beside the effect on steroidogenesis, LXR is able to induce many genes involved in fatty acid biosynthesis. In particular we demonstrated that, in diabetic settings, LXR activation increases SREBP-1c function, restores myelin lipid species, strongly alterated by pathology, and recovers P0 expression levels to normal. Again, these LXR-modulated improvements are associated with restored myelin structure in sciatic nerve and enhanced performance in functional tests such as thermal nociceptive threshold and nerve conduction velocity. Moreover these lesson learned from the protective effects of LXR activation on DPN prompted us to focus our research on the possible cross talk between neurosteroids and lipogenesis. We investigate if neuroactive steroids, in particular DHP and 3α-diol, may exert their protective effects by modulating the myelin lipid profile. Here, we observed that DHP and 3α-diol act on the lipogenic gene expression profile in the sciatic nerve of diabetic rats, restoring alterations in myelin sheath with an amelioration of the diabetic phenotype. Ultimately these results suggest that LXR activation may represent a new pharmacological avenue to exert neuroprotective effects on diabetic peripheral neuropathy.

ROLE OF LIVER X RECEPTOR ACTIVATION ON DIABETIC PERIPHERAL NEUROPATHY / F. Abbiati ; tutor: D. Caruso ; coordinatore: F. Bonomi. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2014 Feb 27. 26. ciclo, Anno Accademico 2013. [10.13130/abbiati-federico_phd2014-02-27].

ROLE OF LIVER X RECEPTOR ACTIVATION ON DIABETIC PERIPHERAL NEUROPATHY

F. Abbiati
2014

Abstract

Diabetic peripheral neuropathy (DPN) is associate with damages and abnormalities in myelin sheath. Similar changes have been observed in the peripheral nerves of streptozotocin (STZ)-treated rats, a model of type 1 diabetes. It is well known that diabetes blunt levels of neuroprotective molecules such as neuroactive steroids and we observed that the pathology induces a different lipid pattern in myelin due to an altered balance between saturated and unsaturated fatty acids, reduces cholesterol levels in myelin sheath and modifies expression of several important genes involved in lipid metabolism such as sterol regulatory element binding protein 1c (SREBP-1c). Liver X Receptor (LXR) is a ligand-activated nuclear receptor that controls cholesterol and lipid metabolism directly regulating the expression of several genes involved in these pathways. In fact LXR family regulates adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that also in sciatic nerve of rat both LRXα and β isoforms are expressed and that these receptors are functional. We observed that activation of LXRs in rat, using a synthetic ligand, is able to increase most of the enzymes involved in steroidogenesis rising neurosteroids levels and triggering protective effect of the sciatic nerve against DPN ameliorating physiological and functional tests. Beside the effect on steroidogenesis, LXR is able to induce many genes involved in fatty acid biosynthesis. In particular we demonstrated that, in diabetic settings, LXR activation increases SREBP-1c function, restores myelin lipid species, strongly alterated by pathology, and recovers P0 expression levels to normal. Again, these LXR-modulated improvements are associated with restored myelin structure in sciatic nerve and enhanced performance in functional tests such as thermal nociceptive threshold and nerve conduction velocity. Moreover these lesson learned from the protective effects of LXR activation on DPN prompted us to focus our research on the possible cross talk between neurosteroids and lipogenesis. We investigate if neuroactive steroids, in particular DHP and 3α-diol, may exert their protective effects by modulating the myelin lipid profile. Here, we observed that DHP and 3α-diol act on the lipogenic gene expression profile in the sciatic nerve of diabetic rats, restoring alterations in myelin sheath with an amelioration of the diabetic phenotype. Ultimately these results suggest that LXR activation may represent a new pharmacological avenue to exert neuroprotective effects on diabetic peripheral neuropathy.
27-feb-2014
Settore BIO/10 - Biochimica
Diabetes ; Neuropathy ; Myelin ; LXR ; Neurosteroids ; Fatty acids
CARUSO, DONATELLA
BONOMI, FRANCESCO
Doctoral Thesis
ROLE OF LIVER X RECEPTOR ACTIVATION ON DIABETIC PERIPHERAL NEUROPATHY / F. Abbiati ; tutor: D. Caruso ; coordinatore: F. Bonomi. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2014 Feb 27. 26. ciclo, Anno Accademico 2013. [10.13130/abbiati-federico_phd2014-02-27].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/232581
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