Role of brown and beige fat in alcoholic liver disease

摘要（说明） 酒精摄入刺激游离脂肪酸（FFA）从白色脂肪组织中释放，并增加 FFAs进入肝细胞，从而促进肝脏脂肪变性和酒精性肝病（ALD）。阻止贩运 肝脏的FFA可能有希望预防/治疗ALD;然而， 对游离脂肪酸的贩运和分销仍然难以控制。最近的研究强调了 棕色脂肪组织（BAT）和米色脂肪在人类和啮齿动物。BAT和米色脂肪保卫体温 通过产热作用保持体内平衡，并通过增加能量消耗防止肥胖。 UCP 1仅在BAT和米色脂肪中表达，并介导热量产生和能量消耗。 UCP 1的缺失损害BAT/米色脂肪功能。在人类中，表达UCP 1的棕色/米色缺陷 脂肪细胞增加肥胖和代谢疾病的风险。令人惊讶的是，BAT和米色脂肪在 尚未检查酒精性肝脏疾病的进展，因为它们主要燃烧游离脂肪酸来促进UCP 1介导的 产热作用我们推测BAT和米色脂肪通过以下方式保护肝脏内环境稳定，防止脂肪变性： 抑制FFA的肝内流。在初步数据中，我们发现BAT和米色脂肪的失活， 通过UCP 1的基因缺失，显著加剧酒精诱导的肝脂肪变性、损伤、炎症， 和纤维化。值得注意的是，酒精摄入大大增加了BAT中UCP 1的表达。酒精也 刺激小鼠BAT和棕色脂肪细胞培养物中的醇代谢酶Cyp 2 E1的表达， 这表明BAT具有内在的酒精敏感能力。此外，阻断交感神经输入到BAT 损害酒精刺激UCP 1表达的能力，表明脑交感神经轴 介导BAT和米色脂肪的酒精刺激。基于这些新发现，我们假设酒精 摄入刺激BAT和米色脂肪直接通过其内在的酒精感应机制， 间接通过脑交感神经通路。BAT和米色脂肪燃烧FFA，从而抑制 将FFA运输到肝脏中并防止ALD。此外，BAT和米色脂肪还分泌 肝脏保护性内分泌因子，保护肝脏免受损伤、炎症和纤维化。该项目将 询问在以下情况下介导BAT/米色脂肪和肝脏之间串扰的潜在机制： ALD。目标1：描述酒精消费如何激活BAT和米色脂肪。我们将检验这个假设， 酒精直接和间接地刺激BAT/米色脂肪。我们将描述的组成部分，直接 间接途径。目的2：描述BAT和米色脂肪如何预防ALD。我们将测试 假设BAT和米色脂肪通过燃烧FFA和分泌肝保护性物质来保护ALD 内分泌因素该项目的成果预计将BAT/米色脂肪定义为未识别的酒精 高级和作为一个新的防御者对ALD，从而打开了一个新的BAT/米色脂肪领域的ALD领域。

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.