内科理论与实践

内科理论与实践 ›› 2025, Vol. 20 ›› Issue (03): 224-231.doi: 10.16138/j.1673-6087.2025.03.07

• 论著 • 上一篇    下一篇

生物钟紊乱与非酒精性脂肪性肝病病理特征的相关性研究

黄磊1a, 张晨莉1a,1b, 阎骅1a, 史冬梅2()   

  1. 1.上海交通大学医学院附属瑞金医院 a.全科医学科；b.消化内科，上海 200025
    2.上海曜影医院全科医学科，上海 200002
  • 收稿日期:2024-08-05 出版日期:2025-06-28 发布日期:2025-09-01
  • 通讯作者: 史冬梅 E-mail:sdm2050@hotmail.com

Correlation study on circadian rhythm disturbance and pathological characteristics of non-alcoholic fatty liver disease

HUANG Lei1a, ZHANG Chenli1a,1b, YAN Hua1a, SHI Dongmei2()   

  1. 1. Department of General Practice; b. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    2. Department of General Medicine, SinoUnited Health, Shanghai 200002, China
  • Received:2024-08-05 Online:2025-06-28 Published:2025-09-01
  • Contact: SHI Dongmei E-mail:sdm2050@hotmail.com

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摘要：

目的：研究生物钟调控与非酒精脂肪性肝病脂质代谢的关键分子机制及其对脂质代谢的影响，为非酒精性脂肪性肝病防治提供一定的依据。 方法：方法：建立高脂饮食+生物钟紊乱（high fat diet + circadian rhythm disturbance, HFC）组、普通饮食+生物钟紊乱（normal chow diet + circadian rhythm disturbance, NC）组、高脂饮食（high fat diet, HF）组、普通饮食（normal chow diet， N）组4组非酒精性脂肪性肝病小鼠模型。采用油红O以及苏木精-伊红染色（hematoxylin and eosin staining，HE）法检测肝脏脂肪沉积情况；采用酶联免疫吸附分析（enzyme-linked immunosorbent assay，ELISA）检测小鼠血清中血脂水平；应用免疫印迹法检测脑和肌肉芳香烃受体核转位样蛋白1(brain and muscle arnt-like 1, BMAL1）基因表达水平，及其与肝脏病理特征的相关性。对HFC组以及HF组采用mRNA生物信息分析技术获取非酒精性脂肪性肝病关键生物钟基因。 结果：生物钟紊乱可导致小鼠体重增加并诱发肥胖，至第15周，HFC组体重超过HF组（t=23.18，P<0.000 1），NC组体重高于N组（t=5.24，P<0.000 1）。生物钟紊乱同时促进肝脏脂质沉积，HFC组随时间延长，肝脏脂肪含量逐渐增多（F=10.13，P<0.05）；NC组脂肪含量亦随时间增加（F=8.89，P<0.05）。生物钟紊乱加剧脂质代谢异常，HFC组小鼠总胆固醇（total cholesterol, TC）以及低密度脂蛋白胆固醇（low density lipoprotein-cholesterol, LDL-C）在ZT0、8、16时均显著高于HF组（F=23.3，P<0.000 1；F=68.1，P<0.000 1）；NC组小鼠TC和LDL-C在ZT0、8、16时均高于N组（F=3.9，P<0.000 1；F=5.8，P<0.000 1）。BMAL1的表达呈节律性波动，HFC组和NC组BMAL1蛋白表达在ZT16时较ZT8时更高，与其脂肪肝的严重程度呈正相关（r=0.995，P=0.022）。 结论：高脂饮食破坏小鼠脂质代谢稳态，而生物钟节律紊乱加重代谢异常程度，增加肝脏脂质沉积，加速脂肪肝进展。生物钟基因BMAL1与非酒精性脂肪性肝病的代谢密切相关。

关键词: 非酒精性脂肪性肝病, 生物钟, BMAL1, 脂质代谢

Abstract:

Objective To investigate the key signal molecules in the regulation of biological clock and lipid metabolism of non-alcoholic fatty liver disease（NAFLD）and its effect on lipid metabolism, to provide insights for the prevention and treatment of NAFLD. Methods The animal models with NAFLD were established and classified, including circadian rhythm disorder + high-fat diet(HFC) group, circadian rhythm disorder + normal diet(NC) group, high-fat diet (HF) group and normal diet (N) group. Hematoxylin and eosin (HE) and oil red O staining were used to detect the fat deposition in the model liver tissues; enzyme-linked immunosorbent assay(ELISA) was used to detect the serum lipids in the mice; immunoblotting was performed to detect the protein expression of brain and muscle arnt-like 1(BMAL1) gene，and the correlation between BMAL1 gene and the liver pathological features was estimate. For the HFC and HF groups, mRNA bioinformatics analysis was performed to identify key circadian clock genes in NAFLD. Results Circadian rhythm disturbance increased body weight and induced obesity in mice. At week 15, the HFC group showed significantly higher weight than the HF group (t=23.18, P<0.000 1), and the NC group exceeded the N group (t=5.24, P<0.000 1). It also promoted hepatic lipid deposition: lipid content progressively increased in the HFC group (F=10.13, P<0.05) and NC group (F=8.89, P<0.05) over time. Moreover, it exacerbated dyslipidemia: TC and LDL-C levels in the HFC group were significantly higher than the HF group at ZT0, ZT8 and ZT16 (F=23.3, P<0.0001; F=68.1, P<0.000 1); similarly, the NC group had elevated TC and LDL-C versus the N group (F=3.9, P<0.000 1; F=5.8, P<0.000 1). BMAL1 expression exhibited rhythmic fluctuations, with higher protein levels at ZT16 than ZT8 in HFC and NC groups, showing a significant positive correlation with fatty liver severity (r=0.995, P=0.022). Conclusions A high-fat diet causes abnormal lipid metabolism in mice; the disturbance of circadian rhythm exacerbates the abnormal lipid metabolism in mice, increases lipid deposition in the liver, and promotes the progression of fatty liver. The biological clock gene BMAL1 is closely related to the metabolism of non-alcoholic fatty liver disease. High expression of BMAL1 may induce fat accumulating in the liver.

Key words: Non-alcoholic fatty liver disease, Circadian rhythm, BMAL1, Lipid metabolism

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