Jeong Byung-Kwan, Choi Won-Il, Choi Wonsuk, Moon Jieun, Lee Won Hee, Choi Chan, Choi In Young, Lee Sang-Hyun, Kim Jung Kuk, Ju Young Seok, Kim Pilhan, Moon Young-Ah, Park Jun Yong, Kim Hail
Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Korea.
Biomedical Research Center, KAIST, Daejeon, Korea.
Nat Commun. 2024 Aug 2;15(1):6506. doi: 10.1038/s41467-024-50660-y.
The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established.
缺乏能够概括整个疾病谱的合适的代谢功能障碍相关脂肪性肝病（MASLD）临床前模型，阻碍了对疾病病理生理学的探索以及有效治疗策略的开发。在此，我们开发了一种小鼠模型（链脲佐菌素联合高脂饮食，STZ + HFD），该模型在代谢功能障碍的背景下逐渐发展为脂肪肝、代谢功能障碍相关脂肪性肝炎（MASH）、肝纤维化和肝细胞癌（HCC）。STZ + HFD小鼠的肝脏转录组特征与伴有2型糖尿病、MASH和MASLD相关HCC的肥胖患者的特征密切相关。饮食改变和替尔泊肽给药可减轻STZ + HFD小鼠的MASH、肝纤维化和肝肿瘤发生。总之，成功建立了一种小鼠模型，该模型概括了在MASLD患者中观察到的主要组织病理学、转录组学和代谢改变。
