肝分泌因子调节脂肪组织代谢的分子机制与生物学功能

Metabolic processes are tightly controlled in cells. They are also regulated through organ-organ communication. Liver is the major organ for lipid biosynthesis, conversion and secretion. Fat is responsible for the storage and oxidation of lipid. The interaction between liver and fat tissues is intimate and important. We have found that in the gp78 liver-specific knockout mice, lipid biosynthesis in liver decreases. However the synthesis of fatty acid in white adipose tissue increases. The expression of UCP1 in brow adipocytes is upregulated and the energy expenditure elevates. These phenomena are partially due to the increasing secretion of FGF21 in liver. We have also found betulin that inhibits lipid biosynthesis in liver causes the elevation of heat production in brown adipose tissue. Together, these results indicate that liver can regulate adipose tissue through producing hepatokines under different lipid levels. However, only a few hepatokines have been identified and the mechanism of liver-fat communication is poorly understood. This proposal will systematically screen and identify the hepatokines whose expression is regulated by lipid level and reveal their functions on regulating adipose tissues. We will investigate the mechanisms of their expression regulated by lipid in liver and their effects on the differentiation of pre-adipocytes and lipid and energy metabolism in adipose tissues. In addition, the roles of these hepatokines in fatty liver, obesity and type 2 diabetes will be investigated.

代谢过程除在细胞内受调控外，还受组织器官之间通讯的调节。肝脏是脂质合成、转化和分泌的主要器官；而脂肪则负责脂质储存与氧化，二者之间的互作非常紧密。我们发现，gp78肝脏特异性敲除小鼠，除肝内脂质合成减少外，还表现为白色脂肪组织脂肪酸合成增加，棕色脂肪中UCP1表达增加，产热增强，部分原因是由于肝脏分泌FGF21增多。同时，我们用脂质合成抑制剂白桦酯醇处理小鼠，降低肝脏脂质水平，也可导致棕色脂肪产热增加。这些结果均表明肝脏脂质代谢改变后，可通过分泌不同因子，调控脂肪组织。但是，只有少数肝分泌因子被发现，肝脏—脂肪互作的机制还所知甚少。本项目将利用小鼠模型，系统性筛选受脂质水平调控的肝分泌因子，揭示它们对脂肪组织的调节作用。探索在肝脏中其表达受脂质水平调节的机理，以及它们对脂肪细胞分化成熟、脂质代谢和能量代谢的调控机制。并利用疾病模型小鼠研究这些肝分泌因子在脂肪肝、肥胖和糖尿病等发生中的作用。

各个器官组织之间的通讯和相互调控对维持机体代谢稳态至关重要。肝脏和白色脂肪组织(white adipose tissue，WAT)是脂质合成的两个重要器官，然而肝脏调控WAT代谢的分子机制并不清楚。我们发现肝分泌因子Gpnmb能够促进WAT的脂质合成。该蛋白注射入小鼠体内可以直接促进 WAT的脂质合成。Gpnmb能够促进WAT的脂质合成，加速饮食诱导的肥胖，导致胰岛素抵抗。为研究中和Gpnmb能否治疗肥胖，我们制备了Gpnmb中和抗体并对饮食诱导的肥胖小鼠进行注射。中和Gpnmb后，肥胖小鼠的WAT脂质合成明显下降，体重同比增长减慢，胰岛素抵抗得到明显改善。我们还在人类疾病中进行了代谢性疾病关联分析。通过ELISA分析收集的330例人体的血清样本，发现肥胖患者的血清Gpnmb浓度偏高。风险分析显示，高浓度的Gpnmb患肥胖、糖尿病等代谢疾病的风险较高。这表明，Gpnmb与肥胖等代谢疾病有较强的相关性。综上所述，本工作通过筛选发现了肝脏分泌蛋白因子Gpnmb促进脂肪组织的脂质合成，加速肥胖和胰岛素抵抗；中和Gpnmb能够减缓肥胖，提高胰岛素敏感性；而且Gpnmb与人群中代谢性疾病的发生密切相关。该工作不仅揭示了机体脂质代谢中肝脏调控白色脂肪组织的分子机制，而且具有潜在的临床意义。