Central nervous system-adipose tissue axis in the pathogenesis of alcoholic liver disease

酒精性肝病发病机制中的中枢神经系统-脂肪组织轴

• 批准号: 10240705
• 负责人: ZHENYUAN SONG
• 金额: $ 35.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240705
• 关键词: Adenovirus Vector; Adipocytes; Adipose tissue; Adrenergic Receptor; Adverse effects; Affect; Agonist; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Attenuated; Brown Fat; Cannulas; Cell Culture Techniques; Cell Line; Chemicals; Chronic; Cirrhosis; Clinical; Coupled; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Denervation; Development; Diet; Disease; Dissociation; Dose; Ensure; Ethanol; Event; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Gene Silencing; Genetic; Health; Human; Hypothalamic structure; Impairment; Individual; Intervention; Investigation; Knockout Mice; Laboratories; Lipolysis; Liver; Liver Failure; Mammals; Modeling; Morbidity - disease rate; Mus; Neuraxis; Norepinephrine; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Physiology; Play; Process; Reporting; Role; Scheme; Steatohepatitis; Sympathetic Nervous System; Testing; Thermogenesis; United States; alcohol effect; alcohol exposure; alcohol response; aldehyde dehydrogenases; analog; base; chronic alcohol ingestion; feeding; implantation; liver injury; mortality; osmotic minipump; response; therapeutic target

Abstract Alcoholic liver disease (ALD) remains an important health problem in the United States. It ranks among the major causes of morbidity and mortality in the world, and affects millions of patients worldwide each year. The disease process is characterized by early steatosis, steatohepatitis, with some individuals ultimately progressing to fibrosis/cirrhosis and liver failure. Currently, there is no accepted therapy available to halt or reverse this process in humans. Adipose tissue dysfunction plays a critical role in the pathogenesis of ALD; however, the exact mechanisms underlying the detrimental effect of alcohol on adipocyte function remain elusive. In mammals, adipose tissues comprise white adipose tissue (WAT) and brown adipose tissue (BAT), which is further categorized into “classical” BAT and “inducible” beige fat. The adipocytes in beige fat are Ucp1-expressing thermogenic adipocytes and can be induced to manifest the phenotypes of classical brown adipocytes via a process called “browning”. Sympathetic nervous system (SNS) is the primary initiator of both lipolysis and browning process through releasing norepinephrine (NE) at target adipose tissues. Physiologically, a tightly-regulated “coupling” between lipolytic and thermogenic machinery activation must be maintained to assure that most fatty acids released from adipose tissue by lipolysis can be ultimately utilized for thermogenesis process/heat production. The promotive effect of chronic alcohol consumption on lipolysis activation has been well- documented, in contrast, its effect on adipose tissue browning/thermogenic process, as well as its potential involvement in the pathogenesis of ALD development, remain unknown. Furthermore, although the profound effect of alcohol on central nervous system (CNS) has been widely reported, whether and how CNS contributes to these processes remain ambiguous. The data obtained recently in my laboratory revealed that ALD development was associated with adipose tissue cAMP/PKA pathway activation. Nevertheless, chronic alcohol exposure inhibited adipose tissue “browning”, implying a “dissociation” between the two physiologically coupled processes in response to increased SNS tone in response to alcohol drinking. Based on our Preliminary Studies, we hypothesize that chronic alcohol consumption activates SNS, however, it “dissociates” the coupling between lipolysis and browning/thermogenesis in adipose tissues, leading to uncontrolled FFAs release and resultant fatty liver and liver damage. This hypothesis will be tested in the following Specific Aims: AIM 1: To determine the critical role of SNS activation in adipose tissue lipolysis and liver pathologies in response to chronic alcohol exposure; AIM 2: To determine the pathological role of impaired browning/thermogenesis process in ALD and mechanism(s) underlying alcohol-triggered uncoupling between lipolysis and browning/thermogenesis; and AIM 3: To elucidate the mechanism(s) underlying alcohol-induced sympathetic activation.

抽象的 酒精性肝病（ALD）仍然是美国的一个重要健康问题。 世界发病率和死亡率的主要原因，并影响全世界数百万患者 疾病过程的特点是早期脂肪变性，脂肪性肝炎，某些个体。 最终进展为纤维化/肝硬化和肝功能衰竭，目前尚无公认的治疗方法。 可用于阻止或逆转人类的这一过程，脂肪组织功能障碍在这一过程中发挥着关键作用。 然而，ALD 的发病机制；酒精对身体有害的确切机制 在哺乳动物中，脂肪细胞的功能仍然难以捉摸，脂肪组织包括白色脂肪组织（WAT）。 棕色脂肪组织（BAT），进一步分为“经典”BAT 和“诱导型”米色 米色脂肪中的脂肪细胞是表达 Ucp1 的产热脂肪细胞，可被诱导产生 交感神经通过称为“褐变”的过程表现出经典棕色脂肪细胞的表型。 神经系统（SNS）是脂肪分解和褐变过程的主要引发者，通过释放 去甲肾上腺素（NE）在目标脂肪组织中的生理学上是一种严格调节的“耦合”。 必须维持脂肪分解和生热机制的激活，以确保大多数脂肪酸 通过脂肪分解从脂肪组织中释放出来，最终可用于产热过程/热量 长期饮酒对脂肪分解激活的促进作用已被证实。 相反，记录了它对脂肪组织褐变/生热过程的影响，以及它的 潜在参与 ALD 发展的发病机制仍不清楚。 酒精对中枢神经系统 (CNS) 的广泛影响已被广泛报道，无论是 中枢神经系统如何促进这些过程仍然不明确。 揭示 ALD 的发展与脂肪组织 cAMP/PKA 通路激活相关。 然而，长期接触酒精会抑制脂肪组织“褐变”，这意味着“解离” 两个生理耦合过程之间的响应增加的 SNS 音调响应 根据我们的初步研究，我们研究了长期饮酒。 激活 SNS，然而，它“解离”了脂肪分解和褐变/产热之间的耦合 脂肪组织，导致不受控制的 FFA 释放并导致脂肪肝和肝损伤。 假设将在以下具体目标中得到检验： 目标 1：确定 SNS 的关键作用 慢性酒精暴露引起的脂肪组织脂肪分解和肝脏病理的激活； 2：确定 ALD 中褐变/生热过程受损的病理作用 机制：酒精潜在触发脂肪分解和褐变/产热之间的解偶联； 目标 3：阐明酒精引起的交感神经激活的机制。