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.

摘要 酒精性肝病（ALD）在美国仍然是一个重要的健康问题。跻身 是世界上发病率和死亡率的主要原因，每年影响全球数百万患者， 年疾病过程的特点是早期脂肪变性，脂肪性肝炎，有些人 最终发展为纤维化/肝硬化和肝功能衰竭。目前，没有公认的治疗方法 可以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起着关键作用。 ALD的发病机制;然而，酒精对ALD的有害影响的确切机制是， 脂肪细胞功能仍然是难以捉摸的。在哺乳动物中，脂肪组织包括白色脂肪组织（WAT）。 和棕色脂肪组织（BAT），其进一步分为“经典”BAT和“诱导型”米色 胖了米色脂肪中的脂肪细胞是表达Ucp 1的产热脂肪细胞，可以被诱导为 通过称为“布朗宁”的过程显示经典棕色脂肪细胞的表型。交感 神经系统（SNS）是脂肪分解和布朗宁过程的主要启动者， 去甲肾上腺素（NE）在目标脂肪组织。从生理学上讲， 必须保持脂解和产热机制的激活，以确保大多数脂肪酸 通过脂解从脂肪组织中释放的脂肪酸最终可用于产热过程/加热 生产长期饮酒对脂解激活的促进作用已经很好- 相反，记录了其对脂肪组织布朗宁/产热过程的影响，以及其 可能参与ALD发展的发病机制，仍然未知。此外，虽然 酒精对中枢神经系统（CNS）的深远影响已被广泛报道，无论 中枢神经系统如何促进这些过程仍不明确。最近在我的实验室获得的数据 显示ALD的发生与脂肪组织cAMP/PKA通路的激活有关。 然而，长期酒精暴露抑制脂肪组织“布朗宁”，这意味着“解离” 在两个生理上耦合的过程之间，响应于增加的SNS音调， 饮酒。根据我们的初步研究，我们假设长期饮酒 激活SNS，然而，它“解离”脂肪分解和布朗宁/产热之间的耦合， 脂肪组织，导致不受控制的FFA释放和由此产生的脂肪肝和肝损伤。这 将在以下具体目标中检验假设：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解和肝脏病理的激活 2：确定ALD中受损的布朗宁/产热过程的病理作用， 脂肪分解和布朗宁/产热之间的酒精触发解偶联的潜在机制; 目的3：阐明酒精诱导交感神经兴奋的机制。