Abstract

BACKGROUND Portal hypertension (PHT) is a life-threatening complication of chronic liver disease, necessitating reliable animal models that mimic its clinical heterogeneity. Classical mouse models like bile duct ligation (BDL) exhibit a low 4-week survival (35%), while carbon tetrachloride (CCl 4 ) models have delayed pathogenesis, requiring ≥ 8 weeks for PHT development, limiting their efficiency. AIM To evaluate the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced mouse model as a biliary PHT model, comparing it to BDL and CCl 4 models. METHODS Mice were assigned to DDC diet, BDL, or CCl 4 groups. Assessments included portal pressure, histological examination of biliary fibrosis and hepatic stellate cell (HSC) activation (desmin expression), scanning electron microscopy for sinusoidal fenestrae and capillarization, endothelial nitric oxide synthase (eNOS) regulation (phosphorylated-eNOS/total eNOS ratio and total eNOS level), ductular reaction, inflammatory infiltration, and portosystemic shunting. Survival rates and operational feasibility (feed-based administration) were evaluated. RESULTS At 4 weeks, DDC induced portal pressure comparable to BDL and CCl 4 . The DDC model showed moderate biliary fibrosis (similar to BDL but less than CCl 4 ) and greater HSC activation than the other two models. Sinusoidal fenestrae reduction and capillarization in DDC matched BDL and CCl 4 models. DDC had decreased phosphorylated-eNOS/total eNOS ratio, while BDL and CCl 4 models exhibited reduced total eNOS. DDC demonstrated robust ductular response, inflammation, and shunting, a hallmark of PHT. Survival was 100% ( vs 35% BDL, 58.3%-66.6% CCl 4 ), with simpler feed-based induction. CONCLUSION The DDC model offers strong biliary PHT relevance, high survival, and efficiency, making it a superior alternative to BDL and CCl 4 models for biliary PHT research.