Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1.
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.


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 LDLs (oxLDLs).


RESULTS
Mice on a high-fat diet have increased oxLDLs and systemic and nerve oxidative stress. They develop nerve conduction velocity (NCV) and sensory deficits prior to impaired glucose tolerance. In vitro, oxLDLs lead to severe DRG neuron oxidative stress via interaction with the receptor lectin-like oxLDL receptor (LOX)-1 and subsequent NAD(P)H oxidase activity. Oxidative stress resulting from oxLDLs 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 oxLDLs that may injure DRG neurons via LOX-1 and contribute to the development of diabetic neuropathy.
Vincent
Andrea M
AM
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. andreav@umich.edu
Hayes
John M
JM
McLean
Lisa L
LL
Vivekanandan-Giri
Anuradha
A
Pennathur
Subramaniam
S
Feldman
Eva L
EL
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D053938:DNA Fragmentation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003929:Diabetic Neuropathies / Q000097:blood / Q000209:etiology* / Q000503:physiopathology*; D004041:Dietary Fats / Q000009:adverse effects; D050171:Dyslipidemias / Q000150:complications*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006614:Hindlimb / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000009:adverse effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000473:pathology; D009431:Neural Conduction / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D008077:Lipoproteins, LDL; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein