Role of brown and beige fat in alcoholic liver disease

摘要(描述) 酒精摄入刺激白色脂肪组织释放游离脂肪酸并增加摄取 游离脂肪酸进入肝细胞，从而促进肝脏脂肪变性和酒精性肝病(ALD)。堵截人口贩运 FFA到肝脏可能有希望预防/治疗ALD；然而，组织和细胞类型 控制FFA的贩运和分配仍然难以捉摸。最近的研究强调了新陈代谢的功能 人类和啮齿动物的棕色脂肪组织(蝙蝠)和米色脂肪。蝙蝠和米色脂肪保护体温 通过生热保持动态平衡，并通过增加能量消耗来预防肥胖。 UCP1只在蝙蝠和米色脂肪中表达，调节热量产生和能量消耗。 UCP1的缺失会损害BAT/米色脂肪的功能。在人类中，表达棕色/米色的UCP1缺乏 脂肪细胞会增加肥胖和代谢性疾病的风险。令人惊讶的是，蝙蝠和米色脂肪在 ALD的进展还没有被研究，因为它们主要燃烧FFA来为UCP1介导的燃料提供燃料 生热作用。我们推测，蝙蝠和米色脂肪通过以下方式保护肝脏动态平衡，防止脂肪变性 抑制游离脂肪酸的肝内流。在初步数据中，我们发现蝙蝠和米色脂肪的失活， 通过UCP1的基因缺失，显著加剧酒精诱导的肝脏脂肪变性，损伤，炎症， 和纤维化症。值得注意的是，酒精摄入显著增加了BAT中UCP1的表达。酒精也是 在小鼠BAT和棕色脂肪细胞培养中刺激酒精代谢酶CYP2E1的表达， 这表明蝙蝠具有内在的酒精感知能力。此外，阻断BAT的交感神经输入 削弱酒精刺激UCP1表达的能力，表明大脑-交感神经轴 调节酒精对蝙蝠和米色脂肪的刺激。根据这些新发现，我们假设酒精 摄入刺激蝙蝠和米色脂肪直接通过其固有的酒精感应机制和 间接地通过脑交感神经通路。蝙蝠和米色脂肪燃烧脂肪酸，从而抑制 将游离脂肪酸贩运到肝脏并预防ALD。此外，蝙蝠和米色脂肪也会分泌 保护肝脏免受损伤、炎症和纤维化的内分泌因子。这个项目将 在以下情况下询问蝙蝠/米色脂肪和肝脏之间的串扰潜在机制 ALD.目标1：描述饮酒如何激活蝙蝠和米色脂肪。我们将检验这一假设 酒精直接或间接地刺激蝙蝠/米色脂肪。我们将描述直接连接的组件的特征 和间接途径。目标2：描述蝙蝠和米色脂肪如何预防ALD。我们将测试 蝙蝠和米色脂肪通过燃烧游离脂肪酸和分泌保肝物质来预防ALD的假说 内分泌因素。该项目的结果预计将把BAT/米色脂肪定义为未被识别的酒精 作为一名资深和新型的ALD防守者，从而在ALD领域开辟了一个新的蝙蝠/米色脂肪区域。

Abstract (Description) Alcohol intake stimulates release of free fatty acids (FFAs) from white adipose tissue and increases uptake of FFAs into hepatocytes, thereby promoting liver steatosis and alcoholic liver disease (ALD). Blocking trafficking of FFAs to the liver likely holds a promise for preventing/treating ALD; however, tissues and cell types that control FFA trafficking and distributions remain elusive. Recent studies highlight the metabolic function of brown adipose tissue (BAT) and beige fat in humans and rodents. BAT and beige fat defend body temperature homeostasis through thermogenesis, and protect against obesity through increasing energy expenditure. UCP1 is expressed exclusively in BAT and beige fat and mediates heat production and energy expenditure. Deletion of UCP1 impairs BAT/beige fat function. In humans, deficiency in UCP1-expressing brown/beige adipocytes increases risk for obesity and metabolic diseases. Surprisingly, the role of BAT and beige fat in ALD progression has not been examined, given that they primarily burn FFAs to fuel UCP1-mediated thermogenesis. We speculated that BAT and beige fat defend liver homeostasis against steatosis by suppressing hepatic influx of FFAs. In the preliminary data, we found that inactivation of BAT and beige fat, through genetic deletion of UCP1, markedly exacerbates alcohol-induced liver steatosis, injury, inflammation, and fibrosis. Remarkably, alcohol intake substantially increases UCP1 expression in BAT. Alcohol also stimulates expression of alcohol metabolic enzyme Cyp2E1 in both mouse BAT and brown adipocyte cultures, suggesting that BAT has intrinsic alcohol-sensing capability. Moreover, blocking sympathetic inputs to BAT impairs the ability of alcohol to stimulate UCP1 expression, indicating that a brain-sympathetic nerve axis mediates alcohol stimulation of BAT and beige fat. Based on these novel findings, we hypothesize that alcohol intake stimulates BAT and beige fat both directly through their intrinsic alcohol-sensing machinery and indirectly via the brain-sympathetic nerve pathways. BAT and beige fat burn FFAs, thereby suppressing trafficking of FFAs into the liver and protecting against ALD. Additionally, BAT and beige fat also secrete hepatoprotective endocrine factors that defend liver against injury, inflammation, and fibrosis. This project will interrogate the underlying mechanisms mediating crosstalk between BAT/beige fat and liver in the context of ALD. Aim 1: Delineate how alcohol consumption activates BAT and beige fat. We will test the hypothesis that alcohol stimulates BAT/beige fat both directly and indirectly. We will characterize the components of the direct and indirect pathways. Aim 2: Delineate how BAT and beige fat protect against ALD. We will test the hypothesis that BAT and beige fat protect against ALD by burning FFAs and secreting hepatoprotective endocrine factors. The outcomes of this project are expected to define BAT/beige fat as unrecognized alcohol senior and as a novel defender against ALD, thereby opening a new BAT/beige fat area in the ALD field.