Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China.
Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing, 100191, China; State Key Laboratory of Vascular Homeostasis and Remodeling, State Key Laboratory of Natural and Biomimetic Drugs, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, 100191, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, Beijing, 100191, China; School of Basic Medical Science, Shihezi University, Shihezi, 83200, Xinjiang, China.
Biochem Biophys Res Commun. 2024 Nov 19;734:150732. doi: 10.1016/j.bbrc.2024.150732. Epub 2024 Sep 21.
This study aims to explore the regulating effect and mechanism of naringenin (NGN) on the hepatic stellate cells (HSCs) apoptosis and its preventive effects on MASH fibrosis. C57BL/6 mice were subjected to either high-fat diet (HFD) plus carbon tetrachloride (CCl) injection (HFD + CCl) for 8 weeks to induce a MASH fibrosis model or bile duct ligation (BDL) to establish a liver fibrosis model, NGN was administered by gavage. LX2 cells were stimulated by oleic acid (OA) and lipopolysaccharide (LPS) (OA + LPS) to study the effects of NGN on activated hepatic stellate cell (HSC). Additionally, LO2 cells stimulated with OA + LPS were used to assess the protective effects of NGN on lipotoxicity of hepatocytes. Our in vivo results showed that NGN administration effectively inhibited mouse liver fibrosis in both of the MASH model and BDL model. The in vitro results indicate that NGN directly inhibited HSCs activation and promoted apoptosis of the activated HSCs, while it suppressed the apoptosis of LO2 cells induced by OA + LPS. The underlying mechanisms were mainly elucidated through the reduction of TAK1 phosphorylation, leading to the downregulation of p-JNK and p-ERK expression. This in turn, inhibited the phosphorylation of FoxO3a and promoted the nuclear localization of FoxO3a. Consequently, this may enhance the transcription of apoptosis-related genes, resulting in the apoptosis of activated HSCs. In conclusion, NGN ameliorates MASH fibrosis by enhancing apoptosis of the activated HSCs. The inhibitory effects of NGN on the TAK1/MAPK/FoxO3a pathway were demonstrated as its preventive mechanisms against MASH fibrosis.
本研究旨在探讨柚皮素（NGN）对肝星状细胞（HSCs）凋亡的调节作用及其对 MASH 纤维化的预防作用。C57BL/6 小鼠接受高脂饮食（HFD）加四氯化碳（CCl）注射（HFD+CCl）8 周，诱导 MASH 纤维化模型，或胆管结扎（BDL）建立肝纤维化模型，给予柚皮素灌胃。用油酸（OA）和脂多糖（LPS）刺激 LX2 细胞（OA+LPS），研究 NGN 对活化的肝星状细胞（HSC）的影响。此外，用 OA+LPS 刺激 LO2 细胞，评估 NGN 对肝细胞脂毒性的保护作用。我们的体内结果表明，NGN 给药可有效抑制 MASH 模型和 BDL 模型中小鼠肝纤维化。体外结果表明，NGN 直接抑制 HSCs 活化并促进活化的 HSCs 凋亡，同时抑制 OA+LPS 诱导的 LO2 细胞凋亡。其潜在机制主要通过降低 TAK1 磷酸化来阐明，导致 p-JNK 和 p-ERK 表达下调。这反过来抑制了 FoxO3a 的磷酸化，促进了 FoxO3a 的核定位。因此，这可能增强凋亡相关基因的转录，导致活化的 HSCs 凋亡。总之，NGN 通过增强活化的 HSCs 的凋亡来改善 MASH 纤维化。NGN 对 TAK1/MAPK/FoxO3a 通路的抑制作用被证明是其预防 MASH 纤维化的机制。
