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已发表论文
雷帕霉素和氯喹可调节高脂/高胆固醇饮食诱导的代谢功能障碍相关脂肪肝小鼠模型中的胰岛素抵抗和肝脂肪变性
Authors Liu Q, Du Q, Yuan X, Zhang T, Li J, Xu J, Xie R
Received 10 May 2025
Accepted for publication 8 October 2025
Published 5 November 2025 Volume 2025:18 Pages 4059—4072
DOI https://doi.org/10.2147/DMSO.S539555
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 5
Editor who approved publication: Professor Jae Woong Sull
Qi Liu,1,* Qian Du,2,* Xiaolu Yuan,3 Ting Zhang,3 Jiajing Li,3 Jingyu Xu,4 Rui Xie2
1Department of Gastroenterology, Zhejiang Provincial People’s Hospital Bijie Hospital, Bijie, Guizhou, People’s Republic of China; 2Department of Endoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 3Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China; 4School of Preclinical Medicine of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jingyu Xu, School of Preclinical Medicine of Zunyi Medical University, No. 6, Xuefu West Road, Xinpu New District, Zunyi, Guizhou, 563003, People’s Republic of China, Email xujingyu_gzzy@126.com Rui Xie, Department of Endoscopy and Digestive System, Guizhou Provincial People’s Hospital, 83 Zhongshan East Road, Yunyan District, Guiyang, Guizhou, 550002, People’s Republic of China, Email xr19841029@aliyun.com
Objective: To establish a short-term high-fat/high-cholesterol (HFHC) diet-induced Metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model, and evaluate the effects of rapamycin (RaPa) and chloroquine (CQ) on this model to explore their therapeutic potential and side effects.
Methods: An early MASLD mouse model was constructed via short-term HFHC diet feeding. Model mice were intraperitoneally injected with RaPa or CQ. Drug effects were analyzed on body weight, liver weight, lipid metabolism-related genes (APOB, FASN, PLIN2), inflammatory factors (IL-6, IL-10), and fibrosis markers (LOX, Col-1α-1, CCL2, TGFβ 1, PDGFRβ, α-SMA) at mRNA and protein levels.
Results: RaPa ameliorated body weight and liver weight in early MASLD mice, downregulated FASN and PLIN2 expression, upregulated IL-10 mRNA levels, and alleviated hepatic steatosis, but induced metabolic disorders such as Insulin resistance and hyperlipidemia. In contrast, CQ promoted FASN and PLIN2 expression, exacerbated hepatic steatosis, reduced IL-10 mRNA levels, and upregulated fibrosis-related markers (LOX, TGFβ 1, PDGFRβ, α-SMA) at both mRNA and protein levels, thereby driving MASLD progression to liver fibrosis. Notably, CQ improved metabolic abnormalities in model mice, including obesity, hyperlipidemia, and Insulin resistance.
Conclusion: RaPa and CQ exhibit dual effects on early MASLD: RaPa alleviates hepatic steatosis but exacerbates metabolic disorders, whereas CQ improves metabolic abnormalities but accelerates liver fibrosis. This paradox highlights the need to balance metabolic regulation and liver injury prevention in MASLD treatment, providing critical experimental insights for targeted drug development.
Keywords: MASLD, MASH, autophagy modulation, rapamycin, chloroquine
1Department of Gastroenterology, Zhejiang Provincial People’s Hospital Bijie Hospital, Bijie, Guizhou, People’s Republic of China; 2Department of Endoscopy and Digestive System, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 3Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China; 4School of Preclinical Medicine of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Jingyu Xu, School of Preclinical Medicine of Zunyi Medical University, No. 6, Xuefu West Road, Xinpu New District, Zunyi, Guizhou, 563003, People’s Republic of China, Email xujingyu_gzzy@126.com Rui Xie, Department of Endoscopy and Digestive System, Guizhou Provincial People’s Hospital, 83 Zhongshan East Road, Yunyan District, Guiyang, Guizhou, 550002, People’s Republic of China, Email xr19841029@aliyun.com
Objective: To establish a short-term high-fat/high-cholesterol (HFHC) diet-induced Metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model, and evaluate the effects of rapamycin (RaPa) and chloroquine (CQ) on this model to explore their therapeutic potential and side effects.
Methods: An early MASLD mouse model was constructed via short-term HFHC diet feeding. Model mice were intraperitoneally injected with RaPa or CQ. Drug effects were analyzed on body weight, liver weight, lipid metabolism-related genes (APOB, FASN, PLIN2), inflammatory factors (IL-6, IL-10), and fibrosis markers (LOX, Col-1α-1, CCL2, TGFβ 1, PDGFRβ, α-SMA) at mRNA and protein levels.
Results: RaPa ameliorated body weight and liver weight in early MASLD mice, downregulated FASN and PLIN2 expression, upregulated IL-10 mRNA levels, and alleviated hepatic steatosis, but induced metabolic disorders such as Insulin resistance and hyperlipidemia. In contrast, CQ promoted FASN and PLIN2 expression, exacerbated hepatic steatosis, reduced IL-10 mRNA levels, and upregulated fibrosis-related markers (LOX, TGFβ 1, PDGFRβ, α-SMA) at both mRNA and protein levels, thereby driving MASLD progression to liver fibrosis. Notably, CQ improved metabolic abnormalities in model mice, including obesity, hyperlipidemia, and Insulin resistance.
Conclusion: RaPa and CQ exhibit dual effects on early MASLD: RaPa alleviates hepatic steatosis but exacerbates metabolic disorders, whereas CQ improves metabolic abnormalities but accelerates liver fibrosis. This paradox highlights the need to balance metabolic regulation and liver injury prevention in MASLD treatment, providing critical experimental insights for targeted drug development.
Keywords: MASLD, MASH, autophagy modulation, rapamycin, chloroquine