Nga Ha Thi, Moon Ji Sun, Tian Jingwen, Lee Ho Yeop, Kim Seok-Hwan, Lee Young-Sun, Jeon Jae-Han, Yi Hyon-Seung
Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, South Korea.
Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea.
Front Med (Lausanne). 2021 May 26;8:672658. doi: 10.3389/fmed.2021.672658. eCollection 2021.
Crosstalk between brown adipose tissue (BAT) and the liver is receiving increasing attention. This study investigated the effect of BAT dysfunction by thermoneutral (TN) housing on liver fibrosis in mice and examined the effect of secreted factors from brown adipocytes on the activation of hepatic stellate cells (HSCs). The carbon tetrachloride (CCl)-induced liver fibrosis mouse model was used to evaluate fibrotic changes in the livers of mice housed under standard and TN conditions. The effect of BAT on the activation of HSCs was examined using cultured cells treated with conditioned media from brown adipocytes. Under TN conditions, mice with CCl-induced liver fibrosis exhibited increased liver injury, collagen deposition, and alpha smooth muscle actin (α-SMA) expression in the liver compared with mice maintained at room temperature. The numbers of liver-infiltrating immune cells and T cells producing IL-17A and IFN-γ were also significantly increased in the livers of mice housed under TN conditions. Treatment of HSCs with conditioned media from brown adipocytes markedly attenuated HSC activation, as shown by down-regulated α-SMA expression at day 4, day 7 and day 10 of culture. At thermoneutrality, with CCl administration, IL-10-deficient mice exhibited more severe liver fibrosis than wild-type mice. Interestingly, conditioned media from IL-10-deficient brown adipocytes could up-regulate the expression of α-SMA and induce HSCs activation. BAT inactivation by thermoneutrality contributes to the activation of pro-inflammatory and pro-fibrotic pathways in mice with CCl-induced liver fibrosis. Normal brown adipocytes secreted factors that impair the activation of HSCs, while this protective effect was lost in IL-10-deficient brown adipocytes. Thus, the BAT-liver axis may serve as a potential therapeutic target for liver fibrosis, and IL-10 may be a key factor regulating the activation of HSCs by BAT.
棕色脂肪组织（BAT）与肝脏之间的相互作用正受到越来越多的关注。本研究调查了热中性（TN）饲养条件导致的BAT功能障碍对小鼠肝纤维化的影响，并检测了棕色脂肪细胞分泌因子对肝星状细胞（HSCs）激活的作用。采用四氯化碳（CCl）诱导的肝纤维化小鼠模型，评估标准饲养条件和TN饲养条件下小鼠肝脏的纤维化变化。使用棕色脂肪细胞条件培养基处理的培养细胞，检测BAT对HSCs激活的影响。在TN条件下，与室温饲养的小鼠相比，CCl诱导的肝纤维化小鼠肝脏损伤增加、胶原沉积增加且α平滑肌肌动蛋白（α-SMA）表达增加。TN饲养条件下小鼠肝脏中浸润的免疫细胞以及产生白细胞介素-17A和干扰素-γ的T细胞数量也显著增加。棕色脂肪细胞条件培养基处理HSCs可显著减弱HSCs激活，培养第4天、第7天和第10天时α-SMA表达下调表明了这一点。在热中性条件下，给予CCl后，白细胞介素-10缺陷小鼠的肝纤维化比野生型小鼠更严重。有趣的是，白细胞介素-10缺陷棕色脂肪细胞的条件培养基可上调α-SMA表达并诱导HSCs激活。热中性导致的BAT失活会促进CCl诱导的肝纤维化小鼠体内促炎和促纤维化途径的激活。正常棕色脂肪细胞分泌的因子会损害HSCs的激活，而在白细胞介素-10缺陷的棕色脂肪细胞中这种保护作用丧失。因此，BAT-肝脏轴可能是肝纤维化的潜在治疗靶点，而白细胞介素-10可能是调节BAT对HSCs激活的关键因素。
