AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis

AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎

基本信息

批准号：
10649275
负责人：
BHUPENDRA S KAPHALIA
金额：
$ 42万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-03 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649275
关键词：
5&apos -AMP-activated protein kinase Acinar Cell Agonist Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcoholic Pancreatitis Alcohols Animal Model Attenuated Automobile Driving Body Burden Carnitine Cessation of life Characteristics Cholesterol Esters Chronic Clinic Clinical Complex Consumption Cytotoxin Deer Mouse Development Diabetes Mellitus Diagnosis Digestion Disease Duodenum Early Diagnosis Enzyme Precursors Enzymes Esters Ethanol Ethanol toxicity Event Exocrine pancreas Fatty Acids Fibrosis Food Future Gland Hepatic Homeostasis Human Immunologics Impairment In Vitro Infiltration Inflammation Inflammatory Infiltrate Inflammatory Response Link Lipase Lipids Malignant neoplasm of pancreas Measures Mediating Metabolic Metabolic Pathway Mitochondria Modality Modeling Molecular Target Nonesterified Fatty Acids Oxidative Phosphorylation Pain Pancreas Pancreatic Injury Pathogenesis Pathologist Pathway interactions Patients Phenotype Prevention Process Recording of previous events Research Personnel Ribonucleotides Signal Transduction Stress Testing Therapeutic Tissue Donors Tissues Toxic effect Transferase Trypsinogen adipokines alcoholic chronic pancreatitis analog attenuation chronic alcohol ingestion chronic pancreatitis comorbidity cost cytotoxicity effective therapy feeding in vivo innovation interstitial lipid metabolism lipidomics long chain fatty acid male mouse model oxidation pharmacologic prevent problem drinker therapeutically effective

项目摘要

Abstract Chronic alcohol intake/abuse costing ~250 billion dollars to the US economy and ~100,000 deaths annually is the major cause of chronic pancreatitis (CP). Alcoholic chronic pancreatitis (ACP) is a serious fibro-inflammatory disorder resulting in exocrine insufficiency and such severe co-morbidities as diabetes and pancreatic cancer. Several patients with a history of chronic alcohol use die even before the disease becomes clinically manifested. The exocrine pancreas, which constitutes ~85% of the gland, is a prime target of alcohol toxicity. Although the amount and duration of alcohol consumed are key factors driving pathogenesis of ACP, the mechanism and metabolic basis of ACP are complex and still not well understood. Besides, no effective therapeutics for ACP is available for the clinics. Chronic alcohol (ethanol, EtOH) consumption in humans impairs hepatic alcohol dehydrogenase (ADH) and increases fatty infiltration and formation of fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) in the pancreas. Recently we found that the six-months-old hepatic ADH1 deficient (ADH-) vs. hepatic ADH normal (ADH+) deer mice fed chronic EtOH for 3 months results in exceedingly high body burden of EtOH, dysregulated pancreatic lipid phenotype including elevated levels of FAEEs, lipotoxic inflammation and mimic several fibro-immunological characteristics of ACP. Besides, we found a decreased expression of carnitine palmitoyl transferase (CPT)1A in the pancreatic tissue of chronic EtOH fed ADH- vs. ADH+ deer mice and in EtOH treated human pancreatic acinar cells (hPACs). Similar findings were observed in pancreatic tissue of donors with a premortem diagnosis of ACP. Furthermore, EtOH-induced AMPKα deactivation and reduced expression of CPT1A was attenuated by AMPKα agonist. Therefore, we hypothesize that attenuation of chronic EtOH-induced inhibition of pancreatic CPT1A by AMPKα agonist prevents dysregulated pancreatic lipid phenotype along with formation of FAEEs and associated lipotoxic inflammation, and fibrosis in alcoholic chronic pancreatitis. In aim 1 we will determine if chronic EtOH reduces the expression of pancreatic CPT1A, causes pancreatic injury, dysregulates lipid phenotype, increases the formation of FAEEs and mitochondrial stress in our ADH- deer mouse model. In aim 2 we will determine if EtOH exposure inhibits CPT1A and causes dysregulated lipid phenotype and formation of FAEEs, cytotoxicity and mitochondrial stress in hPACs, in vitro, to establish that exocrine pancreatic acinar cells are the target of EtOH induced toxicity. In both aims, we will measure above mentioned parameters by attenuating the EtOH induced inhibition of CPT1A and AMPKα inactivation by AMPKα agonist. Our project is innovative because we will identify key lipid metabolic pathways/networks involved in dysregulated pancreatic lipid phenotype in ADH- deer mouse model of alcoholic pancreatitis using cutting edge lipidomic approach. Besides, findings of this project are expected to establish a link between pancreatic CPT1A and AMPKα signaling and dysregulated lipid phenotype in pathogenesis of ACP and develop its therapeutics.

抽象的慢性酒精摄入/滥用每年给美国经济造成约 2500 亿美元的损失，并造成约 10 万人死亡慢性胰腺炎（CP）的主要原因是酒精性慢性胰腺炎（ACP）是一种严重的纤维炎症。导致外分泌功能不全以及糖尿病和胰腺癌等严重并发症的疾病。一些有长期饮酒史的患者甚至在疾病出现临床表现之前就死亡了。外分泌胰腺占腺体的 85%，是酒精中毒的主要目标。饮酒量和饮酒持续时间是 ACP 发病的关键因素，其机制和 ACP 的代谢基础很复杂，目前仍不清楚。此外，ACP 尚无有效的治疗方法。可供诊所使用的酒精（乙醇，EtOH）会损害肝脏。脱氢酶（ADH）并增加脂肪酸渗透和脂肪酸乙酯（FAEE，最近我们在胰腺中发现了六个月大的肝脏 ADH1。缺乏 (ADH-) 与肝 ADH 正常 (ADH+) 鹿小鼠长期饲喂乙醇 3 个月会导致异常结果身体 EtOH 负荷高、胰腺脂质表型失调（包括 FAEE 水平升高）、脂毒性此外，我们还发现 ACP 的一些纤维免疫学特征有所减少。肉毒碱棕榈酰转移酶 (CPT)1A 在慢性 EtOH 喂养 ADH 与对照组胰腺组织中的表达 ADH+ 鹿小鼠和 EtOH 处理的人胰腺腺泡细胞 (hPAC) 中也观察到了类似的结果。死前诊断为 ACP 的捐赠者的胰腺组织此外，EtOH 诱导的 AMPKα。 AMPKα 激动剂可减弱 CPT1A 的失活和表达减少。 AMPKα 激动剂减弱慢性 EtOH 诱导的胰腺 CPT1A 抑制，可防止胰腺脂质表型失调以及 FAEE 的形成和相关的脂毒性在目标 1 中，我们将确定慢性乙醇是否会导致炎症和纤维化。降低胰腺 CPT1A 的表达，导致胰腺损伤，脂质表型失调，增加在目标 2 中，我们将确定 ADH 鹿小鼠模型中 FAEE 的形成和线粒体应激。 EtOH 暴露会抑制 CPT1A 并导致脂质表型失调和 FAEE 形成、细胞毒性和 hPAC 中的线粒体应激，在体外，以确定外分泌胰腺腺泡细胞是在这两个目标中，我们将通过减弱 EtOH 来测量上述参数。 AMPKα 激动剂诱导抑制 CPT1A 和 AMPKα 失活我们的项目是创新的，因为我们。将确定参与ADH-中胰腺脂质表型失调的关键脂质代谢途径/网络使用尖端脂质组学方法建立鹿小鼠酒精性胰腺炎模型此外，这一发现。该项目预计将建立胰腺 CPT1A 和 AMPKα 信号传导与脂质失调之间的联系 ACP 发病机制中的表型并开发其治疗方法。