Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
Air Force Medical University, Xi'an 710032, China.
Phytomedicine. 2024 Jan;123:155145. doi: 10.1016/j.phymed.2023.155145. Epub 2023 Oct 13.
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.
HYPOTHESIS/PURPOSE: This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms.
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.
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.
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.
芝麻酚（SEM）是一种从芝麻中分离出来的天然木脂素化合物，具有很强的抗氧化、调节脂质代谢、降低胆固醇和保肝作用。然而，其抗肝纤维化作用及其机制尚未得到全面阐明。
假说/目的：本研究旨在探讨 SEM 的抗肝纤维化作用及其机制。
采用 TAA 诱导 C57BL/6 小鼠肝纤维化，分别给予 SEM 或姜黄素治疗。用 TGF-β或条件培养基刺激 HSCs，然后分别用 SEM、GW4064、GW3965、雷帕霉素（RA）或 3-甲基腺嘌呤（3-MA）培养。用 SEM、RA 或 3-MA 处理肝纤维化小鼠，以评估 SEM 对自噬的影响。
体外实验中，SEM 显著抑制细胞外基质沉积、P2×7r-NLRP3 和炎症细胞因子。SEM 增加了 FXR 和 LXRα/β 的表达，降低了 MAPLC3α/β 和 P62 的表达，作用类似于 3-MA（自噬抑制剂）。体内实验中，SEM 降低了 TAA 引起的血清转氨酶、组织病理学改变、纤维化、自噬标志物和炎症细胞因子。用 LPS 预处理的 THP-1 条件培养基激活 LX-2，导致自噬标志物和炎症细胞因子显著增加，FXR 和 LXRα/β 表达减少。SEM 可以逆转这些变化，并作用类似于 3-MA、GW4064 或 GW3965。FXR 或 LXR 缺陷减弱了 SEM 对激活的 LX-2 中 α-SMA、MAPLC3α/β、P62 和 IL-1β 的调节作用。在激活的 THP-1 中，FXR 缺失可降低 LXR 的表达，反之亦然。在激活的 MΦ 中缺失 FXR 或 LXR 可降低激活的 LX-2 中 FXR 和 LXR 的表达。在激活的 MΦ 中缺失 FXR 或 LXR 也减弱了 SEM 对 α-SMA、MAPLC3α/β、P62、caspase-1 和 IL-1β 的调节作用。体内实验中，SEM 通过抑制纤维化、自噬和炎症显著逆转肝纤维化。
SEM 可通过抑制纤维化、自噬和炎症来调节肝纤维化。FXR/LXR 轴介导的自噬抑制有助于 SEM 对肝纤维化的调节，特别是基于涉及 HSCs-巨噬细胞的串扰。SEM 可能是一种有前途的治疗候选药物，其机制将为肝纤维化治疗提供新的方向或策略。
