Pharmaceutical optimization of chitosan tablets is associated with reduced circulating bile acids and fibrosis-related molecular signatures in non-alcoholic steatohepatitis rats.

Non-alcoholic steatohepatitis (NASH) is a progressive liver disease associated with metabolic dysfunction and cardiovascular complications. Although chitosan is widely used as an oral lipid-regulating adsorbent, the influence of tablet disintegration and dispersion properties on systemic biological responses remains unclear. In this study, rapidly dispersible granulated chitosan tablets (GCT) and poorly dispersible non-granulated chitosan tablets (NCT) were evaluated in a high-fat and high-cholesterol (HFC) diet-fed SHRSP5/Dmcr rat model of NASH, with metformin as a reference drug. A corn oil loading test identified 40 mg/day GCT as the effective dose, significantly suppressing postprandial triglyceride elevation. In NASH rats, both chitosan formulations and metformin reduced serum total cholesterol, whereas only chitosan decreased serum total bile acids. In hepatic tissue, chitosan and metformin selectively attenuated α-smooth muscle actin (α-SMA) expression, while other fibrosis-related and inflammatory markers were unchanged. Notably, coordinated suppression of fibrosis-related genes in cardiac tissue occurred exclusively in the GCT-treated group. Tablet disintegration and dispersion were associated with reduced circulating bile acids and formulation-dependent lipid handling, along with selective extrahepatic molecular signatures in NASH. Cardiac changes were limited to transcript-level modulation, without evidence of structural remodeling or causality. Further studies are required to clarify the mechanisms.