CCAAT/增强子结合蛋白α通过调控SREBP-1c/FASN/ACC轴促进代谢相关脂肪性肝病小鼠肝脏脂肪变性

doi:10.12122/j.issn.1673-4254.2026.10.11

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (10): 2415-2423.doi: 10.12122/j.issn.1673-4254.2026.10.11

• • 上一篇

CCAAT/增强子结合蛋白α通过调控SREBP-1c/FASN/ACC轴促进代谢相关脂肪性肝病小鼠肝脏脂肪变性

张雷英¹(), 邹立洋¹(), 周玲玲²(), 马欣³, 刘晓敏¹, 姚欢¹, 庄远¹(), 于洋¹()

^1.解放军总医院第一医学中心输血医学科，北京 100853
^2.解放军总医院医疗保障中心医学工程科，北京 100853
^3.保定市第四中心医院全科医学科，河北保定 072350

收稿日期:2026-01-04 出版日期:2026-10-20 发布日期:2026-10-26
通讯作者: 庄远,于洋 E-mail:zhangleiying0312@163.com;zouliyang823@163.com;lingling19870702@163.com;zhuangyuan0215@126.com;yuyangpla301@163.com
作者简介:张雷英，主治医师，E-mail: zhangleiying0312@163.com
邹立洋，主治医师，E-mail: zouliyang823@163.com
周玲玲，医师， E-mail: lingling19870702@163.com。
第一联系人：同等贡献：:张雷英、邹立洋、周玲玲共同为第一作者

CEBPA promotes hepatic steatosis in metabolic dysfunction-associated fatty liver disease in mice via the SREBP-1c/FASN/ACC axis

Leiying ZHANG¹(), Liyang ZOU¹(), Lingling ZHOU²(), Xin MA³, Xiaomin LIU¹, Huan YAO¹, Yuan ZHUANG¹(), Yang YU¹()

^1.Department of Blood Transfusion, First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
^2.Department of Medical Engineering, Medical Supplies Center of PLA General Hospital, Beijing 100853, China
^3.Department of General Practice, Baoding Fourth Central Hospital, Baoding 072350, China

Received:2026-01-04 Online:2026-10-20 Published:2026-10-26
Contact: Yuan ZHUANG, Yang YU E-mail:zhangleiying0312@163.com;zouliyang823@163.com;lingling19870702@163.com;zhuangyuan0215@126.com;yuyangpla301@163.com

摘要/Abstract

摘要：

目的探讨 CCAAT/增强子结合蛋白α（CEBPA）在代谢相关脂肪性肝病（MAFLD）中的作用，并分析其是否通过调控固醇调节元件结合蛋白-1c（SREBP-1c）参与肝细胞脂肪生成。方法将8周龄雄性C57BL/6J小鼠随机分为对照组和高脂饮食组，每组6只。对照组给予普通维持饲料，高脂饮食组给予含45%脂肪的高脂饲料，连续饲养8周后检测血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）和游离脂肪酸（FFA）水平，并采用Western blotting和油红O染色检测肝组织中CEBPA、SREBP-1c、脂肪酸合酶（FASN）、乙酰辅酶A羧化酶（ACC）的蛋白表达及肝脏脂质沉积。体外实验采用HepG2细胞，分别设置阴性对照组、CEBPA干扰组、CEBPA过表达组、SREBP-1c干扰组、SREBP-1c过表达组、CEBPA干扰联合SREBP-1c过表达组、CEBPA过表达联合SREBP-1c干扰组；部分细胞给予棕榈酸钠/油酸钠处理，终浓度为0.75 mmol/L，处理48 h，以建立体外高脂刺激模型。采用实时荧光定量聚合酶链式反应（qPCR）、Western blotting和油红O染色检测CEBPA、SREBP-1c、FASN、ACC表达及细胞内脂质沉积变化。结果与对照组比较，高脂饮食组小鼠血清TC、TG、LDL-C和FFA水平均升高，差异有统计学意义（P<0.0001）；肝组织CEBPA、SREBP-1c、FASN和ACC蛋白表达水平均高于对照组，油红O染色显示高脂饮食组肝组织脂质沉积增加。与阴性对照组比较，CEBPA干扰组SREBP-1c、FASN和ACC mRNA表达降低（均P<0.01），SREBP-1c和FASN蛋白表达降低（P<0.05），ACC蛋白表达降低（P<0.01）；CEBPA过表达组SREBP-1c、FASN和ACC mRNA表达升高（P<0.001），相应蛋白表达升高（均P<0.05）。与阴性对照组比较，SREBP-1c干扰组FASN和ACC表达降低，SREBP-1c过表达组FASN和ACC表达升高；在棕榈酸钠/油酸钠诱导的高脂刺激条件下，上述变化方向仍一致。挽救实验显示，与CEBPA干扰组比较，CEBPA干扰联合SREBP-1c过表达组FASN和ACC表达升高；与CEBPA过表达组比较，CEBPA过表达联合SREBP-1c干扰组FASN和ACC表达降低。结论 CEBPA 可能通过调控 SREBP-1c/FASN/ACC 轴促进肝细胞脂肪生成。该调控关系在基础及高脂条件下均得到支持，提示 CEBPA-SREBP-1c 通路可能参与 MAFLD 肝脏脂肪变性的发生。

Abstract:

Methods To investigate the role of CCAAT/enhancer-binding protein alpha (CEBPA) in metabolic dysfunction-associated fatty liver disease (MAFLD) and whether CEBPA promotes hepatocellular lipogenesis by regulating sterol regulatory element-binding protein-1c (SREBP-1c). Methods Eight-week-old male C57BL/6J mice were assigned to a control group fed a standard diet or a MAFLD model with high-fat diet (HFD) feeding. Hepatic lipid accumulation and the expression of key molecules in the CEBPA/SREBP-1c pathway were assessed using serum biochemical analysis, Western blotting, and Oil Red O staining. In HepG2 cells, CEBPA and SREBP-1c expression was manipulated by plasmid-mediated overexpression or RNA interference. A sodium palmitate/sodium oleate-induced lipid-overload model was used to mimic lipid overload in vitro. Quantitative PCR, Western blotting, Oil Red O staining, and reciprocal rescue experiments were performed to explore the regulatory relationship between CEBPA and SREBP-1c and their effects on lipogenic markers. Results HFD-fed mice developed marked hepatic steatosis with increased serum TC, TG, LDL-C, and FFA levels, significantly upregulated hepatic protein expression of CEBPA, SREBP-1c, fatty acid synthase (FASN), and acetyl-CoA carboxylase (ACC), and enhanced lipid deposition. In HepG2 cells, SREBP-1c knockdown reduced FASN and ACC expression, whereas SREBP-1c overexpression increased their expression in both basal and lipid-overload conditions. Similarly, CEBPA knockdown suppressed SREBP-1c, FASN, and ACC expression and reduced intracellular lipid accumulation, while CEBPA overexpression produced the opposite effects. Rescue experiments showed that SREBP-1c overexpression partially reversed the inhibitory effects of CEBPA knockdown on FASN and ACC, whereas SREBP-1c silencing attenuated CEBPA-induced upregulation of these lipogenic molecules. Conclusion CEBPA promotes hepatic lipogenesis possibly by regulating the SREBP-1c/FASN/ACC axis in both basal and lipid-overload conditions, suggesting that the CEBPA-SREBP-1c pathway contributes to hepatic steatosis in MAFLD and represents a potential therapeutic target.

Key words: metabolic dysfunction-associated fatty liver disease, CCAAT/enhancer-binding protein alpha, sterol regulatory element-binding protein 1c, fatty acid synthesis, lipid metabolism

张雷英, 邹立洋, 周玲玲, 马欣, 刘晓敏, 姚欢, 庄远, 于洋. CCAAT/增强子结合蛋白α通过调控SREBP-1c/FASN/ACC轴促进代谢相关脂肪性肝病小鼠肝脏脂肪变性[J]. 南方医科大学学报, 2026, 46(10): 2415-2423.

Leiying ZHANG, Liyang ZOU, Lingling ZHOU, Xin MA, Xiaomin LIU, Huan YAO, Yuan ZHUANG, Yang YU. CEBPA promotes hepatic steatosis in metabolic dysfunction-associated fatty liver disease in mice via the SREBP-1c/FASN/ACC axis[J]. Journal of Southern Medical University, 2026, 46(10): 2415-2423.

图/表 4

图1 CEBPA 对 SREBP-1c、FASN、ACC 表达及细胞脂质沉积的影响

Fig.1 Effects of CEBPA on SREBP-1c, FASN, and ACC expression and intracellular lipid accumulation in HepG2 cells. A, B: Efficiency of CEBPA knockdown and detected by qPCR and Western blotting. C: Expression levels of SREBP-1c, FASN and ACC after CEBPA knockdown or overexpression detected by qPCR and Western blotting. D: Intracellular lipid accumulation observed using Oil Red O staining. The right panels show enlarged views (Original magnification: ×400) of the red dashed boxes in the left panels (×100). Data are presented as Mean±SD (n=3). *P<0.05, **P<0.01, ***P<0.001 vs control group.

图2 SREBP-1c 对 FASN、ACC 表达及细胞脂质沉积的影响

Fig.2 Effects of SREBP-1c on FASN, ACC expression and intracellular lipid accumulation in HepG2 cells. A, B: Knockdown and overexpression efficiency of SREBP-1c detected by qPCR and Western blotting. C: Expression levels of FASN and ACC in HepG2 cells in routine culture conditions detected by qPCR and Western blotting. D: FASN and ACC protein expression in HepG2 cells with high-lipid stimulation detected by Western blotting. E: Intracellular lipid accumulation in HepG2 cells in routine culture and high-lipid conditions observed by Oil Red O staining. The right panels show enlarged views (×400; Scale bar=50 μm) of the red dashed boxes in the left panels (×100; Scale bars=100 μm). Data are presented as Mean±SD (n=3). **P<0.01, ***P<0.001 vs control group.

图3 CEBPA 通过 SREBP-1c 调控 FASN 和 ACC 的表达

Fig.3 CEBPA regulates FASN and ACC expression through SREBP-1c. A: FASN and ACC mRNA levels in different treatment groups detected by qPCR. B: FASN and ACC protein levels detected by Western blotting. C: Densitometric analysis of Western blot bands. Data are presented as Mean±SD (n=3). **P<0.01, ***P<0.001 vs control group.

图4 高脂饮食诱导 MAFLD 小鼠血脂异常、肝脏脂质沉积及相关蛋白表达变化

Fig.4 High-fat diet induces dyslipidemia, hepatic lipid accumulation and related protein expression changes in MAFLD mice. A: Changes in mouse body weight. B-E: Serum levels of TC, TG, LDL-C and FFA. F: Hepatic protein expression of CEBPA, SREBP-1c, FASN and ACC detected by Western blotting. G: Hepatic lipid accumulation observed by Oil Red O staining. The right panels show enlarged views (×400; Scale bar=50 μm) of the red dashed boxes in the left panels (×100; Scale bars=100 μm). Data are presented as Mean±SD (n=6). *P<0.05, **P<0.01, ***P<0.001 vs control group.

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CCAAT/增强子结合蛋白α通过调控SREBP-1c/FASN/ACC轴促进代谢相关脂肪性肝病小鼠肝脏脂肪变性

CEBPA promotes hepatic steatosis in metabolic dysfunction-associated fatty liver disease in mice via the SREBP-1c/FASN/ACC axis

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