Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy

摘要 糖尿病前期--一种先于2型糖尿病的疾病--影响着8000多万美国人。外围 神经病变是糖尿病并发症，其导致由于外周神经损伤而导致的肢体感觉丧失。 2型糖尿病是一种慢性的糖尿病性疾病，它的发病率很高。尽管流行， 周围神经病变的严重程度，目前没有疾病修饰选项。新的治疗靶点 因此对未来的治疗至关重要。血脂异常的特征是 血浆中的饱和脂肪酸，导致鞘脂水平改变。神经酰胺是一种 对神经元具有脂毒性鞘脂。饱和脂肪酸的积累导致线粒体 功能障碍和细胞凋亡，并可能在周围神经病变的发展中发挥核心作用。 然而，单不饱和脂肪酸在体外保护神经元免受神经酰胺介导的毒性，可能是通过 细胞内脂滴的形成。利用单不饱和脂肪酸抑制神经酰胺积累 因此，补充可能是使神经酰胺谱正常化和预防神经酰胺代谢紊乱的有效策略。 周围神经病变我们假设糖尿病前期的周围神经病变是毒性的结果， 神经酰胺在体内神经元中的积累。我们进一步假设，补充糖尿病前期小鼠， 单不饱和脂肪酸将增强神经元中的脂滴合成，以防止神经酰胺积聚 以及随后的神经毒性。我们将通过以下方式检验这些假设：1）测定神经酰胺的分布， 在血浆和外周神经中均具有神经病变的糖尿病前期小鼠，2）评价 单不饱和脂肪酸补充对糖尿病前期小鼠神经病变期间神经酰胺积累的影响， 以及3）确定神经酰胺损害周围神经系统以及 确定单不饱和脂肪酸改善这种损伤的机制。所有这些 研究将证明血脂异常在周围神经病变的发展中起着中心作用， 为未来的治疗提供了直接的治疗靶点。

ABSTRACT Prediabetes – a condition that precedes type 2 diabetes – affects more than 80 million Americans. Peripheral neuropathy is a diabetic complication that results in a loss of sensation in the limbs due to peripheral nerve damage, and it can develop in both type 2 diabetic as well as prediabetic patients. Despite the prevalence and severity of peripheral neuropathy, there are currently no disease-modifying options. Novel therapeutic targets are therefore of critical importance for future treatments. Dyslipidemia is characterized by increased levels of saturated fatty acids in the plasma, resulting in altered levels of sphingolipids. Ceramides are one type of sphingolipid that are lipotoxic to neurons. Accumulation of saturated fatty acids leads to mitochondrial dysfunction, and cellular apoptosis and may play a central role in the development of peripheral neuropathy. However, monounsaturated fatty acids protect neurons from ceramide-mediated toxicity in vitro, likely via the formation of intracellular lipid droplets. Reversal of ceramide accumulation using monounsaturated fatty acid supplementation may therefore be an effective strategy for normalizing ceramide profiles and preventing peripheral neuropathy. We hypothesize that peripheral neuropathy in prediabetes is the result of toxic ceramide accumulation in neurons in vivo. We further hypothesize that supplementing prediabetic mice with monounsaturated fatty acids will enhance lipid droplet synthesis in neurons to prevent ceramide accumulation and subsequent neurotoxicity. We will test these hypotheses by: 1) determining the ceramide profile of prediabetic mice with neuropathy in both plasma and peripheral nerves, 2) evaluating the efficacy of monounsaturated fatty acid supplementation on ceramide accumulation in prediabetic mice during neuropathy, and 3) determining the mechanisms by which ceramides damage the peripheral nervous system as well as determining the mechanisms by which monounsaturated fatty acid ameliorate this damage. Together, these studies will demonstrate that dyslipidemia plays a central role in the development of peripheral neuropathy and provide an immediate therapeutic target for future treatments.