Fig 2: Graphical abstract. Gypenosides treatment upregulates the SHP level and downregulates the SREBP1 level, thereby decreasing SCD1 and FASN expression and inhibiting hepatic lipid synthesis. Meanwhile, gypenosides can upregulate the expression of PPARa and CPT1 and enhance fatty acid oxidation, gypenosides can also upregulate LPL and MTTP expression, which led to the promotion of lipid decomposition. In addition, gypenosides treatment could significantly upregulate FXR-mediated bile acid pathways, thereby maintaining bile acid homeostasis. FXR, farnesoid X receptor; SHP, small heterodimer partner; SREBP1, sterol-regulatory element-binding protein 1; SCD1, stearyl coenzyme A desaturation enzyme 1; FASN, fatty acid synthetase; PPARa, peroxisome proliferator-activated receptor alpha; CPT1, carnitine palmitoyl transferase 1; LPL, lipoprotein lipase; MTTP, microsomal triglyceride transfer protein. CYP7A1, cholesterol 7-alpha hydroxy-lase; BSEP, bile salt export protein

Fig 3: Changes in FGF15, FGFR4, KLB, CYP7A1, NTCP, and BSEP protein content in liver tissues among the different experimental groups. a Bar chart representing the relative CYP7A1 protein expression level in liver tissue, b relative NTCP protein expression level, c relative BSEP protein expression level, d relative FGF15 protein expression level, e relative FGFR4 protein expression level, and f relative KLB protein expression level in liver tissue. g Representative autoradiograph image of western blotting with the different antibodies. **P < 0.01, vs control group; ##P < 0.01, #P < 0.05, vs HFD group. Data are presented as mean ± standard deviation, n = 3. C, control; HFD, high-fat diet; Gyp, gypenosides; OCA, obeticholic acid

Fig 4: SMS1 deficiency-mediated hepatocyte impairmentLiver sections from 6-month-old WT, Sms2 KO, and Sms1/Sms2 KO female mice were utilized.(A) Na+-taurocholate co-transporting polypeptide (NTCP) immunostaining for hepatocyte basal membrane.(B) Bile salt export pump (BSEP) immunostaining for hepatocyte apical membrane. The pictures are the representatives of four mice/group.(C) Plasma was collected from WT, Sms2 KO, and Sms1/Sms2 KO mice, and jaundice was observed.(D) Fluorogram of plasma bilirubin (conjugated) levels.(E) Fluorogram of plasma total bile acid levels.(F and G) Fluorogram of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Data are represented as mean ± SD, n = 4–6, *p < 0.01.

Fig 5: Changes in the liver tissue levels of FXR, SHP, CYP7A1, BSEP, FGFR4, NTCP, and KLB proteins and ileal tissue levels of FGF15 with intervention of GC or OCA in wild type and FXR-/- mouse NAFLD models. (A) Western blot picture of wild-type mice. (B) Western blot picture of FXR-/- mice. (C) Quantified data of FXR protein in liver tissues. (D1, D2) Quantified data of SHP protein in liver tissues. (E1, E2) Quantified data of CYP7A1 protein in liver tissues. (F1, F2) Quantified data of BSEP protein in liver tissues. (G1, G2) Quantified data of NTCP protein in liver tissues. (H1, H2) Quantified data of FGF15 protein in ileal tissues; (I1, I2) Quantified data of FGFR4 protein in liver tissues. (J1, J2) Quantified data of KLB protein in liver tissues. Abbreviations: NAFLD, non-alcoholic fatty liver disease; ND, normal diet; HFD, high-fat diet; GC, geniposide and chlorogenic acid combination treatment; OCA, obeticholic acid; FXR-/-, FXR knockout.*p < 0.05 and **p < 0.01 (n = 3 per group).