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Dyslipidemia-Induced Neuropathy in Mice: the Role of oxLDL/LOX-1

Authors Andrea M. Vincent, John M. Hayes, Lisa L. McLean, Anuradha Vivekanandan-Giri, Subramaniam Pennathur, and Eva L. Feldman Submitted By Eva Feldman on 1/12/2009 Status Published Journal Diabetes Year 2009 Date Published 10/1/2009 Volume : Pages 58(10) : 2376 - 2385 PubMed Reference Abstract Objective: Neuropathy is a frequent and severe complication of diabetes. Multiple metabolic defects in type 2 diabetic patients result in oxidative injury of dorsal root ganglia (DRG) neurons. Our previous work focused on hyperglycemia clearly demonstrates induction of mitochondrial oxidative stress and acute injury in DRG neurons; however, this mechanism is not the only factor that produces neuropathy in vivo. Dyslipidemia also correlates with the development of neuropathy, even in pre-diabetic patients. This study was designed to explore the contribution of dyslipidemia in neuropathy. Research Design and Methods: Mice (n=10) were fed a control (10%kcal%fat) or high fat (45%kcal%fat) diet to explore the impact of plasma lipids on the development of neuropathy. We also examined oxidized lipid-mediated injury in cultured DRG neurons from adult rat using oxidized low density lipoproteins (oxLDL). Results: Mice on a high fat diet have increased oxLDL and systemic and nerve oxidative stress. They develop nerve conduction velocity (NCV) and sensory deficits prior to impaired glucose tolerance. In vitro, oxLDL lead to severe DRG neuron oxidative stress via interaction with the receptor LOX-1 and subsequent NAD(P)H oxidase activity. Oxidative stress resulting from oxLDL and high glucose is additive. Conclusions: Multiple metabolic defects in type 2 diabetes directly injure DRG neurons through different mechanisms that all result in oxidative stress. Dyslipidemia leads to high levels of oxLDL that injure DRG neurons via LOX-1 and contribute to the development of diabetic neuropathy.

Investigators with authorship
Name Institution Eva Feldman University of Michigan

Complications
All ComplicationsBioinformatics BoneCardiomyopathy CardiovascularGastro-Intestinal (GI) NephropathyNeuropathy & Neurocognition Pediatric Endocrinology Retinopathy UropathyWound Healing

Genes
Symbol Description Olr1 oxidized low density lipoprotein (lectin-like) receptor 1