背景:Sesamol(SEM),一种从芝麻中分离出的天然木酚素化合物,具有很强的抗氧化性能,调节脂质代谢,降低胆固醇和肝脏保护。然而,其抗肝纤维化作用及机制尚未全面阐明。
目的:本研究旨在探讨SEM的抗肝纤维化及其潜在机制。
方法:TAA诱导C57BL/6小鼠肝纤维化,然后服用SEM或姜黄素,分别。用TGF-β或条件培养基刺激HSC,然后用扫描电镜培养,GW4064,GW3965,雷帕霉素(RA)或3-甲基腺嘌呤(3-MA),分别。肝纤维化小鼠也给予SEM,RA或3-MA来评估SEM对自噬的影响。
结果:体外,SEM显著抑制细胞外基质沉积,P2×7r-NLRP3和炎性细胞因子。SEM增加FXR和LXRα/β的表达,降低MAPLC3α/β和P62的表达,作为3-MA(自噬抑制剂)。在体内,SEM降低血清转氨酶,组织病理学改变,纤维发生,TAA引起的自噬标志物和炎性细胞因子。用LPS引发的THP-1条件培养基激活LX-2,导致自噬标志物和炎性细胞因子显著增强,FXR和LXRα/β表达降低。SEM可以逆转这些变化,并起到3-MA的作用,GW4064或GW3965。FXR或LXR的缺乏减弱了SEM对α-SMA的调节,MAPLC3α/β,激活的LX-2中的P62和IL-1β。在活化的THP-1中,FXR的缺乏可以降低LXR的表达,反之亦然。激活的MΦ中FXR或LXR的缺乏降低了激活的LX-2中FXR和LXR的表达。激活的MΦ中缺乏FXR或LXR也减弱了SEM对α-SMA的调节,MAPLC3α/β,P62、caspase-1和IL-1β。在体内,SEM通过FXR/LXR和自噬显著逆转肝纤维化。
结论:SEM可以通过抑制纤维化来调节肝纤维化,自噬和炎症。FXR/LXR轴介导的自噬抑制有助于调节SEM对抗肝纤维化,特别是基于参与HSCs-巨噬细胞的串扰。SEM可能是一个前瞻性的治疗候选,其机制将为肝纤维化治疗提供新的方向或策略。
BACKGROUND: Sesamol (SEM), a natural lignan compound isolated from sesame, has strong anti-oxidant property, regulating lipid metabolism, decreasing cholesterol and hepatoprotection. However, its anti-hepatic fibrosis effect and mechanisms have not been comprehensively elucidated.
OBJECTIVE: This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms.
METHODS: C57BL/6 mice with hepatic fibrosis were induced by TAA, then administrated with SEM or curcumin, respectively. HSCs were stimulated by TGF-β or conditioned medium, and then cultured with SEM, GW4064, GW3965, Rapamycin (RA) or 3-methyladenine (3-MA), respectively. Mice with hepatic fibrosis also were administrated with SEM, RA or 3-MA to estimate the effect of SEM on autophagy.
RESULTS: In vitro, SEM significantly inhibited extracellular matrix deposition, P2 × 7r-NLRP3, and inflammatory cytokines. SEM increased FXR and LXRα/β expressions and decreased MAPLC3α/β and P62 expressions, functioning as 3-MA (autophagy inhibitor). In vivo, SEM reduced serum transaminase, histopathology changes, fibrogenesis, autophagy markers and inflammatory cytokines caused by TAA. LX-2 were activated with conditioned medium from LPS-primed THP-1, which resulted in significant enhance of autophagy markers and inflammatory cytokines and decrease of FXR and LXRα/β expressions. SEM could reverse above these changes and function as 3-MA, GW4064, or GW3965. Deficiency of FXR or LXR attenuated the regulation of SEM on α-SMA, MAPLC3α/β, P62 and IL-1β in activated LX-2. In activated THP-1, deficiency of FXR could decrease the expression of LXR, and vice versa. Deficiency of FXR or LXR in activated MΦ decreased the expressions of FXR and LXR in activated LX-2. Deficiency FXR or LXR in activated MΦ also attenuated the regulation of SEM on α-SMA, MAPLC3α/β, P62, caspase-1 and IL-1β. In vivo, SEM significantly reversed hepatic fibrosis via FXR/LXR and autophagy.
CONCLUSIONS: SEM could regulate hepatic fibrosis by inhibiting fibrogenesis, autophagy and inflammation. FXR/LXR axis-mediated inhibition of autophagy contributed to the regulation of SEM against hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. SEM might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis treatment.