HCBP6激活棕色脂肪改善非酒精性脂肪肝病的作用机制研究

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by excessive accumulation of triglycerides in the liver. Previous studies have found that activation of brown adipose tissue (BAT) can be effective in the treatment of fatty liver caused by obesity.However, the regulatory factors that activating BAT are rarely reported and their regulatory molecular mechanisms have not been elucidated.Our previous results showed that HCBP6 was the key regulator of liver lipid metabolism, and the expression of UCP1 in the HCBP6 knockout mice was significantly decreased, suggesting that the activity of BAT was closely related to HCBP6. HCBP6 might increase BAT activity and improve the hepatic lipid metabolism and NAFLD. Therefore, in current study, we aim to identify HCBP6 improves NAFLD by activating brown adipose tissue and the molecular mechanism. Outcome of current proposal will provide certain theoretical basis and new technical support and, may open up new avenues for the prevention and treatment of NAFLD.

非酒精性脂肪肝病（NAFLD）是以甘油三酯在肝内过度贮积而引起的慢性肝病。既往研究发现激活棕色脂肪（BAT）可有效治疗由肥胖引起的脂肪肝，但激活BAT的调控因子鲜有报道且其调控分子机制尚未阐明。我们前期研究结果表明，HCBP6作为肝脏脂代谢稳态中的关键调节基因，其敲除小鼠BAT特异性产热基因UCP1表达量显著下降，提示BAT的活性与HCBP6密切相关，HCBP6可能具有上调BAT活性，改善肝脏脂质代谢以及NAFLD的作用。本项目将利用棕色脂肪细胞模型明确HCBP6与BAT活性的相关性，利用BAT特异性表达HCBP6转基因小鼠深入研究HCBP6促进BAT活性改善NAFLD的生理作用，揭示HCBP6调控BAT活性的分子机制。本项目可为NAFLD等代谢综合症的预防治疗提供一定的理论依据，并为NAFLD治疗提供新思路。

本项目以阐述HCBP6激活棕色脂肪来改善NAFLD以及相关脂代谢紊乱症状为目的，从动物水平和细胞水平利用生理学、细胞生物学、分子生物学和生物信息学等手段开展研究，探讨HCBP6与棕色脂肪活性的相关性；同时从HCBP6调控小鼠代谢特征出发，探讨HCBP6对棕色脂肪活性的调控机制，以期从增强机体能量消耗的角度探寻防治NAFLD的新途径。通过本项目的实施，明确了HCBP6与棕色脂肪活性以及NAFLD的相关性，阐明了肝脏脂质稳态调节因子HCBP6的生理作用，并以HCBP6为靶点，筛选出对NAFLD具有治疗作用的人参皂苷提取物Rh2。本研究表明HCBP6在NAFLD的发生中起着保护作用，首次证明了HCBP6与棕色脂肪活性以及非酒精性脂肪肝存在负相关性；HCBP6基因敲除后，小鼠棕色脂肪活性下降并且更易发生糖脂代谢紊乱，即HCBP6在维持糖脂代谢稳态中发挥重要作用；且HCBP6具有抑制炎症反应的作用；同时，人参皂苷Rh2增强了HCBP6的表达，进而改善由HFD诱导的NAFLD代谢异常，为NAFLD的防治提供了重要理论基础和治疗靶点，对相关代谢疾病的防治、缓解患者的经济和社会压力具有重要意义，并具备将靶点药物进行临床转化的前景。