六维磷脂通过抑制p38 MAPK/CD36轴改善酒精性肝病脂质代谢紊乱的机制研究

肝脏 ›› 2026, Vol. 31 ›› Issue (2): 271-278.

六维磷脂通过抑制p38 MAPK/CD36轴改善酒精性肝病脂质代谢紊乱的机制研究

耿雯倩, 王阳, 李家玺, 袁晓雪, 杨松

100020 北京首都医科大学附属北京地坛医院,北京市感染性疾病研究中心(耿雯倩,王阳,李家玺,袁晓雪);100029 北京中日友好医院感染性疾病科(杨松)

收稿日期:2025-03-01 出版日期:2026-02-28 发布日期:2026-04-17
通讯作者: 杨松,Email:sduyangsong@163.com;袁晓雪,Email:yuanxiaoxue1@ccmu.edu.cn
基金资助:
青海省昆仑英才高端创新创业人才(领军人才柔性引进2024);北京市高层次公共卫生人才建设项目(学科骨干-02-30,XKGG-02-30); 北京市属医院科研培育计划(PX2022071);首都医科大学科研培育基金(PYZ24164);首都医科大学临床专科学院(系)培养基金开放课题(CCMU2024ZKYXY015);首都医科大学附属北京地坛医院院内科研基金“启航计划”项目(DTQH-202404)

Hexavalent phospholipids ameliorate alcoholic liver disease by modulating lipid metabolism via the p38 MAPK/CD36 axis

GENG Wen-qian¹, WANG Yang¹, LI Jia-xi¹, YUAN Xiao-xue¹, YANG Song²

1. Beijing Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100020, China;
2. China-Japan Friendship Hospital, Division of Infectious Diseases, Beijing 100029, China

Received:2025-03-01 Online:2026-02-28 Published:2026-04-17
Contact: YANG Song,Email:sduyangsong@163.com;YUAN Xiao-xue,Email:yuanxiaoxue1@ccmu.edu.cn

摘要/Abstract

摘要： 目的探讨六维磷脂(HexaV)治疗酒精相关性肝病(ALD)的作用及其分子机制,重点解析其对脂质代谢紊乱的调控途径。方法 SPF级C57BL/6雄性小鼠30只随机分为3组:对照组(生理盐水灌胃,5 g/kg,每日一次,连续8周),ALD模型组(32.5%无水乙醇灌胃,5 g/kg,每日一次,连续8周),ALD+HexaV组[32.5%无水乙醇(5 g/kg)+HexaV(0.8 mg/g),每日一次,连续8周]。收集小鼠血清和肝组织,检测小鼠血清生化指标。通过HE和油红O染色观察小鼠肝组织病理变化。对小鼠肝组织进行转录组测序,q-PCR和Western Blot检测相关基因的mRNA和蛋白表达。结果与对照组相比,ALD模型组血浆ALT(U/L)水平显著增加(430.90±150.56 vs. 228.80 ±115.87,t=2.450,P=0.036);而在HexaV处理后,血浆ALT(U/L)和AST(U/L)水平相较于对照组和ALD模型组均显著降低(ALT:ALD+HexaV组 vs. 对照组: 34.15±19.79 vs. 228.80±115.87,t=4.766,P=0.001;ALD+HexaV组 vs. ALD组: 34.15±19.79 vs. 430.90±150.56,t=7.470,P<0.001)(AST:ALD+HexaV组 vs. 对照组: 246.00±95.40 vs. 690.80±148.28,t=6.667,P<0.001;ALD+HexaV组 vs. ALD组: 246.00±95.40 vs. 639.40±160.57,t=5.764,P<0.001)。与对照组相比,ALD模型组TC(mmol/L)含量显著升高(3.61±0.20 vs. 1.80±0.34,t=8.529,P<0.001),而在ALD+HexaV组中,血浆TC(mmol/L)(ALD+HexaV组 vs. ALD组: 3.27±0.12 vs. 3.61±0.20,t=2.894,P=0.034)和TG(ALD+HexaV组 vs. ALD组: 0.53±0.03 vs. 0.67±0.06,t=3.575,P=0.011)水平相较于ALD组均显著降低。HE染色和油红O染色观察发现,HexaV可改善小鼠肝脏病变和脂质沉积。转录组测序数据表明ALD模型组与ALD+HexaV组存在66个共同的差异基因,其中51个差异基因在ALD模型组升高,而在ALD+HexaV组中降低;15个基因在ALD模型组中下调,而在ALD+HexaV组中上调。KEGG富集分析显示,差异基因主要富集于脂质代谢以及炎症等相关通路。差异基因的GSEA富集分析结果显示,脂肪消化与吸收、脂质与动脉粥样硬化、PPAR信号通路均在ALD模型组被激活,但在ALD+HexaV组中被逆转。CD36在上述三个通路中均被富集,其表达量在ALD模型组中升高,而在ALD+HexaV组中显著降低。差异基因富集分析显示MAPK信号通路显著富集。Western Blot结果显示,与对照组相比,p-38 MAPK在ALD模型组上调,经HexaV处理后下调。结论 HexaV通过调控p38 MAPK-CD36信号通路轴,改善酒精诱导的肝脂质代谢紊乱和脂肪变性,为ALD治疗提供了新靶点和潜在药物。

Abstract: Objective To investigate the hepatoprotective effects of HexaV in ALD and elucidate its underlying molecular mechanisms, with particular focus on its regulatory pathways in lipid metabolic dysregulation. Methods 30 male SPF-grade C57BL/6 mice were randomly divided into three groups: the control group (normal saline, 5 g/kg, once daily for 8 weeks), the ALD model group (32.5% absolute ethanol, 5 g/kg, once daily for 8 weeks), and the ALD + HexaV group (32.5% absolute ethanol (5 g/kg) + HexaV (0.8 mg/g), once daily for 8 weeks). Mouse serum and liver tissues were collected, and biochemical indicators in mouse serum were detected. Pathological changes in mouse liver tissues were observed through HE and Oil Red O staining. Transcriptome sequencing, q-PCR and Western Blot were performed on mouse liver tissues to detect the mRNA and protein expression of related genes. Results Compared to the control group, alcohol treatment increased plasma ALT (U/L) levels (430.90±150.56 vs. 228.80 ±115.87, t=2.450, P=0.036). After HexaV treatment, plasma ALT (U/L) (ALD+HexaV group vs. control group: 34.15±19.79 vs. 228.80±115.87, t=4.766, P=0.001; ALD+HexaV group vs. ALD group: 34.15±19.79 vs. 430.90±150.56, t=7.470,P<0.001) and AST (U/L) (ALD+HexaV group vs. control group: 246.00±95.40 vs. 690.80±148.28, t=6.667, P<0.001; ALD+HexaV group vs. ALD group: 246.00±95.40 vs. 639.40±160.57, t=5.764, P<0.001) levels were reduced compared to both the control group and the ALD model group. Compared to the control group, the ALD model group showed a significant increase in TC (mmol/L) content (3.61±0.20 vs. 1.80±0.34, t=8.529,P<0.001). In the ALD+HexaV group, plasma TC (mmol/L) (ALD+HexaV group vs. ALD group: 3.27±0.12 vs. 3.61±0.20, t=2.894, P=0.034) and TG (mmol/L) (ALD+HexaV group vs. ALD group: 0.53±0.03 vs. 0.67±0.06, t=3.575, P=0.011) levels were significantly reduced compared to the ALD group. Histological assessment (H&E and Oil Red O staining) confirmed HexaV-mediated attenuation of liver injury and steatosis in ALD mice. RNA-seq analysis identified 66 consensus DEGs, with 51 showing reversal of ALD-induced upregulation and 15 exhibiting rescure of ALD-suppressed expression following HexaV treatment. KEGG pathway analysis identified significant enrichment of DEGs in lipid metabolic and pro-inflammatory cascades. GSEA confirmed marked activation of atherogenic pathways (Fat digestion and absorption Lipid and atherosclerosis, PPAR signaling pathway) in ALD mice, with complete reversal following HexaV intervention. Ranscriptomic enrichment analysis revealed significant involvement of the MAPK signaling pathway. Western Blot confirmed p38 hyperphosphorylation in ALD mice, which was attenuated by HexaV treatment. Conclusion Our study demonstrates that HexaV attenuates alcoholic steatosis through selective inhibition of the p38 MAPK-CD36 axis, revealing both a druggable pathway in ALD pathogenesis and a clinically actionable therapeutic strategy.

Key words: Hexavitamin soya Lecithin, Alcohol-associated liver disease, Lipid metabolism, CD36, p38 MAPK signaling pathway

耿雯倩, 王阳, 李家玺, 袁晓雪, 杨松. 六维磷脂通过抑制p38 MAPK/CD36轴改善酒精性肝病脂质代谢紊乱的机制研究[J]. 肝脏, 2026, 31(2): 271-278.

GENG Wen-qian, WANG Yang, LI Jia-xi, YUAN Xiao-xue, YANG Song. Hexavalent phospholipids ameliorate alcoholic liver disease by modulating lipid metabolism via the p38 MAPK/CD36 axis[J]. Chinese Hepatolgy, 2026, 31(2): 271-278.

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