Fig 2: PPARα represses and FXR induces coagulation factor synthesis. (A) Primary mouse hepatocytes treated with 20 μM of the PPARα agonist WY‐14643 or 5 μM of the FXR agonist GW4064 exhibit decreased and increased expression, respectively, of Fga and F11 (n = 6). Expression of known FXR or PPARα target genes is shown in Supporting Fig. S3 as positive controls. (B) Functional role of the IR‐1 motif in the regulatory region of mouse Fga and F11 for PPARα or FXR activity in HeLa cells (n = 6). One‐way analysis of variance followed by Sidak’s multiple comparisons test; ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05. Data are mean + SD. Regulatory regions were identified by in silico analyses illustrated in Supporting Fig. S4. Confirmatory studies performed in AML12 cells are shown in Supporting Fig. S5.

Fig 3: LPLFD plasma protein alterations include decreased coagulation factors. Plasma proteome analysis visualized by (A) heat map and (B) PCA plot reveals that sex differences account for the most variation between groups and that nutritional status accounts for striking differences in male but not female mice. (C) Pathway analyses of 116 altered plasma proteins reveal “Complement and coagulation cascades” as the top perturbed pathway in malnourished male mice. (D) Plasma INR of mice receiving control diet or the LPLFD (n = 5‐8). (E,F) Expression of hepatic mRNA (n = 6) and plasma protein (n = 3‐4) of the coagulation factors Fga and F11 are decreased in malnourished male mice but not female mice. These two genes were found to be decreased in malnourished male mice on an 18‐gene qPCR panel (Supporting Fig. S2). Data in (D,E) are mean + SD. Student t test; **P < 0.01 compared to control mice of the same sex. Abbreviation: FDR, false discovery rate.