title: Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation.
abstract: Diabetic peripheral neuropathy (DPN) is characterized by myelin abnormalities; however, the molecular mechanisms underlying such deficits remain obscure. To uncover the effects of diabetes on myelin alterations, we have analyzed myelin composition. In a streptozotocin-treated rat model of diabetic neuropathy, analysis of sciatic nerve myelin lipids revealed that diabetes alters myelin's phospholipid, FA, and cholesterol content in a pattern that can modify membrane fluidity. Reduced expression of relevant genes in the FA biosynthetic pathway and decreased levels of the transcriptionally active form of the lipogenic factor sterol-regulatory element binding factor-1c (SREBF-1c) were found in diabetic sciatic nerve. Expression of myelin's major protein, myelin protein zero (P0), was also suppressed by diabetes. In addition, we confirmed that diabetes induces sciatic nerve myelin abnormalities, primarily infoldings that have previously been associated with altered membrane fluidity. In a diabetic setting, synthetic activator of the nuclear receptor liver X receptor (LXR) increased SREBF-1c function and restored myelin lipid species and P0 expression levels to normal. These LXR-modulated improvements were associated with restored myelin structure in sciatic nerve and enhanced performance in functional tests such as thermal nociceptive threshold and nerve conduction velocity. These findings demonstrate an important role for the LXR-SREBF-1c axis in protection from diabetes-induced myelin abnormalities.
authors.affiliation: Department of Pharmacological Sciences,  Università degli Studi di Milano, Milano,  Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Cermenati
authors.forename: Federico
authors.initials: F
authors.lastname: Abbiati
authors.forename: Solei
authors.initials: S
authors.lastname: Cermenati
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Brioschi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Volonterio
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Enrique
authors.initials: E
authors.lastname: Saez
authors.forename: Emma
authors.initials: E
authors.lastname: De Fabiani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Crestani
authors.forename: Luis M
authors.initials: LM
authors.lastname: Garcia-Segura
authors.forename: Roberto C
authors.initials: RC
authors.lastname: Melcangi
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D005786:Gene Expression Regulation; D008055:Lipids / Q000737:chemistry; D000071518:Liver X Receptors; D008297:Male; D018993:Myelin P0 Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000473:pathology; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin
chemical_list: D008055:Lipids; D000071518:Liver X Receptors; C560548:Mpz protein, rat; D018993:Myelin P0 Protein; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D013311:Streptozocin; D002784:Cholesterol; D013230:Stearoyl-CoA Desaturase; D011494:Protein Kinases; C033288:(acetyl-CoA carboxylase) kinase