CDAHFD-induced Rat MASH Model

Metabolic Dysfunction-Associated Steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is the progressive inflammatory stage of metabolic dysfunction-associated steatotic liver disease (MASLD). It is characterized by hepatic steatosis (≥5% fat accumulation), inflammation, hepatocyte injury (ballooning), and fibrosis, which can progress to cirrhosis and hepatocellular carcinoma (HCC).


CDAHFD-induced rat MASH model


The choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced rat model is a widely used preclinical system for studying metabolic dysfunction-associated steatohepatitis (MASH), particularly for investigating steatohepatitis, fibrosis progression, and therapeutic interventions. This model efficiently recapitulates key features of human MASH within a relatively short time frame (6–12 weeks).

 

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Fig.1 Body weight and serum ALT, AST, TC, TG, HDL-C and LDL-C of CDAHFD-induced rat MASH model

 

Body weight curve of CDAHFD-induced rat MASH model is shown in Fig. 1A. The serum level of AST and ALT were significantly higher in CDAHFD-induced MASH rats compared to the CD group, while the serum TC, TG, HDL-C, and LDL-C level is lower (Fig. 1B). Data were presented by mean ± SEM, N=8-30. *, p < 0.05; **, p < 0.01; ***, p < 0.001 and ****, p < 0.0001

 

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Fig.2 Histological observation of CDAHFD-induced rat MASH model


Obvious lipid droplet deposition and fibrous tissue hyperplasia were observed in liver of CDAHFD-induced rat MASH model via Pathological staining (HE and Sirius Red staining, Fig. 2A). The Liver/body weight ratio of CDAHFD-induced MASH model is higher than that of CD group as well as the kidney/body weight ratio. Data presented by mean ± SEM, N=3. *, p<0.05; **, p<0.01; ***, p<0.001 and ****, p<0.0001.


Pharmacodynamic evaluation Firsocostat(MGL3196) on CDAHFD-induced rat MASH model


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Fig.3 Overview of pharmacodynamic evaluation on CDAHFD-induced rat MASH model

 

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Fig.4 Body weight of CDAHFD-induced rat MASH model after SAME treatment.


There is no significant difference between the model group and the Firsocostat treated group in body weight. Data were presented by mean ± SEM, N=14-20.

 

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Fig.5 Serum ALT, AST, TC, TG, HDL-C and LDL-C of CDAHFD-induced rat MASH model after Firsocostat treatment


Firsocostat administration reduced serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the CDAHFD-induced rat MASH model, whereas triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) profiles remained unaltered. Data were presented by mean ± SEM, N=14-20. *, p < 0.05; **, p < 0.01; ***, p < 0.001 and ****, p < 0.0001.

 

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Fig.6 The Liver/body weight% and kidney/body weight% of CDAHFD-induced rat MASH model after Firsocostat treatment


The Liver/body weight and kidney/body weight of CDAHFD induced rat MASH model decreased after 6 weeks Firsocostat treatment. Data were presented by mean ± SEM, N=8-20. *, p < 0.05; **, p < 0.01; ***, p < 0.001 and ****, p < 0.0001

 

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Fig.7 Histological observation of CDAHFD induced rat MASH model after Firsocostat treatment


After six weeks of Firsocostat administration, no significant improvement in the histopathological NAFLD activity score was observed in CDAHFD-induced rat MASH models (Fig. 7A). However, significant reductions in fibrosis score and α-SMA mRNA expression were detected, suggesting a selective antifibrotic effect (Fig. 7B). Data were presented by mean ± SEM, N=6. *, p < 0.05; **, p < 0.01; ***, p < 0.001 and ****, p < 0.0001

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