Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy

摘要 糖尿病前期是一种先于2型糖尿病的疾病，影响着8000多万美国人。外围 神经病变是一种糖尿病并发症，由于周围神经的作用，导致四肢失去知觉。 损害，它可以在2型糖尿病和糖尿病前期患者中发展。尽管流行和 对于严重的周围神经病变，目前还没有改善疾病的选择。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 血浆中的饱和脂肪酸，导致神经鞘脂脂水平改变。神经酰胺是一种 对神经元有脂毒作用的神经鞘磷脂。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的发展中发挥中心作用。 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。单不饱和脂肪酸逆转神经酰胺蓄积 因此，补充可能是使神经酰胺谱正常化和预防 周围神经病。我们假设糖尿病前期的周围神经病变是中毒的结果。 神经酰胺在体内神经元中的蓄积。我们进一步假设，给糖尿病前期小鼠补充 单不饱和脂肪酸可促进神经元脂滴合成，防止神经酰胺蓄积 以及随之而来的神经毒性。我们将通过以下方式验证这些假设：1)确定神经酰胺的分布 糖尿病前期小鼠同时存在血浆和周围神经病变，2)评估 补充单不饱和脂肪酸对糖尿病前期小鼠神经病变期间神经酰胺蓄积的影响 以及3)确定神经酰胺损害周围神经系统的机制以及 确定单不饱和脂肪酸改善这种损害的机制。加在一起，这些 研究将证明血脂异常在周围神经病变的发生和发展中起核心作用。 为未来的治疗提供一个直接的治疗目标。

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.