The CGA combination enhances bile acids alternative biosynthesis pathway and alleviates MASH induced by methionine-choline-deficient diet

Objective CGA combination consisting of Cordyceps sinensis polysaccharide, gypenosides, and amygdalin, is derived from Fuzheng Huayu capsule (a traditional Chinese medicine approved for liver fibrosis) via previous Uniform Design Experimentation. The effect of CGA on metabolic dysfunction-associated steatohepatitis (MASH) and the potential mechanism based on bile acids (BAs) alternative biosynthesis pathway—farnesoid X receptor (FXR) axis are investigated here. Methods Alanine aminotransferase, hepatic triglyceride, malondialdehyde (MDA), BAs, fatty acids oxidation (FAO) activity, mRNA of inflammatory cytokines, α-smooth muscle actin (α-SMA), transforming growth factor-β, collagen type I, and FAO enzymes were detected. Liver sections underwent hematoxylin–eosin, Oil Red O, and Sirius red staining, and immunohistochemistry assay of F4/80 and α-SMA. Protein expression of peroxisome proliferator-activated receptor α (PPAR-α), FXR, BAs biosynthesis enzymes, small heterodimer partner (SHP), bile salt export pump (BSEP), adenosine triphosphate-binding cassette sub-family B member 4 (ABCB4) and nuclear factor-kappa B were detected. Key findings CGA ameliorated MASH, restoring FAO, PPAR-α, and FXR, accompanied by increased chenodeoxycholic acid proportion in the FXR agonist BAs pool, BAs alternative biosynthesis, and the FXR targets including SHP, BSEP, and ABCB4. Conclusion CGA ameliorates MASH, promoting the hepatic BAs alternative biosynthesis pathway to activate FXR-PPARα restoring FAO.