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Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1
Andrea M Vincent1, John M Hayes, Lisa L McLean
1Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. andreav@umich.edu
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 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.
Insights
Dyslipidemia contributes to diabetic neuropathy by increasing oxidized low-density lipoproteins (oxLDLs), which cause oxidative stress in dorsal root ganglia (DRG) neurons. This damage occurs independently of high blood sugar, highlighting a distinct mechanism in neuropathy development.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Oxidative Stress
Background:
- Diabetic neuropathy is a severe complication linked to metabolic defects in type 2 diabetes.
- Oxidative injury to dorsal root ganglia (DRG) neurons is a key factor, with hyperglycemia previously shown to induce mitochondrial oxidative stress.
- Dyslipidemia, a condition of abnormal blood lipid levels, also correlates with neuropathy, even in pre-diabetic stages.
Purpose of the Study:
- To investigate the specific contribution of dyslipidemia to the development of diabetic neuropathy.
- To explore the mechanisms by which altered lipid profiles might injure nerve cells.
Main Methods:
- Mice were fed either a control or high-fat diet to assess the impact of plasma lipids on neuropathy development.
- Cultured rat DRG neurons were exposed to oxidized low-density lipoproteins (oxLDLs) to examine lipid-mediated injury in vitro.
- Nerve conduction velocity and sensory deficits were measured in mice.
Main Results:
- High-fat diet in mice led to increased oxLDLs, systemic oxidative stress, and nerve oxidative stress.
- Mice on a high-fat diet exhibited nerve conduction and sensory deficits before impaired glucose tolerance.
- In vitro, oxLDLs induced significant DRG neuron oxidative stress through the LOX-1 receptor and NAD(P)H oxidase activation.
- The oxidative stress from oxLDLs and high glucose was additive.
Conclusions:
- Dyslipidemia contributes to diabetic neuropathy through elevated oxLDLs, which injure DRG neurons.
- Oxidized lipids may damage DRG neurons via the LOX-1 receptor pathway, representing a distinct mechanism of neuropathy.
- Multiple metabolic defects in type 2 diabetes, including dyslipidemia, converge on oxidative stress to damage neurons and cause neuropathy.
