Abstract：
Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro, hepatic stellate cell (HSC) activation was stimulated with TGF-β and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo, C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial-mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.
摘要：
肝纤维化是对慢性肝损伤和炎症的代偿反应，建议将饮食干预作为基本预防策略之一。覆盆子酮（RK）是一种芳香化合物，首先从覆盆子中分离出来，广泛用于制备食品香料。本研究探讨了RK抗肝纤维化的肝保护作用和潜在机制。体外，用TGF-β刺激肝星状细胞（HSC）活化，并用RK培养，法尼醇X受体（FXR），或过氧化物酶体增殖物激活受体γ辅激活因子1-α（PGC-1α）激动剂或抑制剂，分别。在体内,从第1周到第5周用100/200mg/kg的硫代乙酰胺(TAA)腹膜内注射C57BL/6小鼠。从第2周至第5周,每天一次对小鼠胃内施用RK或Cur。在激活的HSC中，RK抑制细胞外基质（ECM）的积累，炎症,上皮-间质转化(EMT)过程。RK既激活了FXR/PGC-1α，又调节了它们的串扰，它们的抑制剂和激动剂证实了这一点。FXR或PGC-1α的缺乏也减弱了RK对激活的HSC的逆转的作用。RK也降低血清ALT/AST水平，肝脏组织病理学改变,ECM积累，炎症,和由TAA引起的小鼠EMT。FXR/PGC-1α的双重激活可能是RK抗肝纤维化的关键靶点。最重要的是,这些发现支持了RK作为肝纤维化饮食干预新候选药物的潜力.
