Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy

糖尿病前期和神经病变中的鞘脂和脂肪酸生物学

• 批准号: 10612104
• 负责人: Amy E. Rumora
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612104
• 关键词: Affect; American; Apoptosis; Biology; Ceramides; Complication; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Dietary Intervention; Disease; Dyslipidemias; Economic Burden; Fatty Acids; Foundations; Future; Goals; High Fat Diet; In Vitro; Individual; Knockout Mice; Limb structure; Lipids; Mediating; Mentors; Metabolic dysfunction; Mitochondria; Monounsaturated Fatty Acids; Morphology; Motor; Mus; Nerve; Nervous System control; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Obese Mice; Obesity; Pathway interactions; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phase; Plasma; Play; Prediabetes syndrome; Prevalence; Productivity; Research; Role; Saturated Fatty Acids; Sensory; Severities; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sphingolipids; Spinal Ganglia; Structure; Supplementation; Symptoms; Testing; Toxic effect; Training; Transcript; Type 2 diabetic; United States; Unsaturated Fatty Acids; afferent nerve; career; diabetic patient; diet-induced obesity; dihydroceramide desaturase; efficacy evaluation; fatty acid supplementation; improved; in vivo; lipidomics; mass spectrometric imaging; mitochondrial dysfunction; mouse model; neurotoxic; neurotoxicity; new therapeutic target; peripheral nerve damage; prevent; sciatic nerve; sural; sural nerve; targeted treatment; therapeutic target; transcriptomics

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.

抽象的 糖尿病前期的疾病（在2型糖尿病之前）会影响超过8000万美国人。外围 神经病是一种糖尿病并发症，导致周围神经引起的四肢感觉丧失 损害，并且可以在2型糖尿病患者和糖尿病前患者中发展。尽管率很高和 周围神经病的严重程度，目前尚无疾病改良的选择。新型热目标 因此，对于将来的治疗至关重要。血脂血症的特征是水平升高 血浆中的饱和脂肪酸，导致鞘脂的水平改变。神经酰胺是一种 鞘脂对神经元具有脂肪毒性。饱和脂肪酸的积累导致线粒体 功能障碍和细胞凋亡，可能在周围神经病的发展中起核心作用。 然而，单不饱和脂肪酸保护神经元免受神经酰胺介导的体外毒性，可能是通过 细胞内脂质液滴的形成。使用单不饱和脂肪酸逆转神经酰胺的积累 因此，补充可能是使神经酰胺概况归一化和防止的有效策略 周围神经病。我们假设糖尿病前期的周围神经病是有毒的结果 神经元在体内的神经酰胺积累。我们进一步假设用 单不饱和脂肪酸将增强神经元中的脂质液滴合成，以防止神经酰胺积累 和随后的神经毒性。我们将通过以下方式测试这些假设：1）确定 血浆和周围神经中神经病前糖尿病小鼠，2）评估效率 神经病期间糖尿病小鼠的神经酰胺积累的单不饱和脂肪酸补充， 3）确定神经酰胺破坏周围神经系统以及 确定单不饱和脂肪酸改善这种损害的机制。在一起，这些 研究将表明，血脂异常在周围神经病的发展中起着核心作用 为将来的治疗提供直接的治疗靶标。

项目成果

A High-Fat Diet Disrupts Nerve Lipids and Mitochondrial Function in Murine Models of Neuropathy.

• DOI: 10.3389/fphys.2022.921942
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4