Fig. 3. Nutrient regulation of bile acid synthesis, insulin signaling, and mechanistic target of rapamycin complex 1 (mTORC1) signaling. Feeding induces cholesterol 7α-hydroxylase (CYP7A1) but inhibits sterol 12α-hydroxylase (CYP8B1), while fasting inhibits CYP7A1 but induces CYP8B1. Feeding and fasting cycles affect bile acid synthesis and composition, which in turn regulate hepatic lipid and glucose metabolism. After feeding and during the postprandial state, bile acids are released from the gallbladder to aid in nutrient absorption. In hepatocytes, CYP7A1 and bile acid synthesis are stimulated to activate farnesoid X receptor (FXR) signaling and insulin/insulin receptor substrate 1 (IRS1)-AKT-phosphoinositide 3-kinase (PI3K) signaling. Insulin signaling inhibits mTORC1/protein S6 kinase (S6K) signaling and steroid regulatory element binding protein 1c (SREBP1c)-mediated lipogenesis. During the late post-prandial state, FXR induces fibroblast growth factor 19 (FGF19) to inhibit CYP7A1 and bile acid synthesis via FGF receptor 4 (FGFR4)/β-Klotho/extracellular regulated kinase 1 and 2 (ERK1/2) signaling. During fasting and prolonged starvation, free fatty acids released from adipose triglycerides activate peroxisome proliferator-activated receptor γ (PPARγ) in adipose tissue and PPARα in hepatocytes, and induce FGF21. FGF21 induces peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to stimulate mitochondrial oxidative phosphorylation and energy production. FGF21 also inhibits mTORC1 signaling to stimulate insulin signaling. In enterocytes, FXR induces ceramides, which activate mTORC1/S6K signaling and stimulate processing of full length SREBP1c to its nuclear form (nSREBP1), stimulating lipogenesis. During fasting, CYP8B1 is induced and increases synthesis of cholic acid (CA) and deoxycholic acid (DCA). DCA activates intestinal FXR and ceramide synthesis. CYP8B1 inhibits FGF21 and activates mTORC1 signaling via inhibition of PPARα. CDCA, chenodeoxycholic acid; TCA, taurocholic acid; TGR5, Takeda G protein-coupled receptor 5; CREBP, cAMP response element binding protein; DIO2, deiodinase type 2; T, taurine; TCDCA, taurochenodeoxycholic acid; LCA, lithocholic acid; DCA, deoxycholic acid.