Fig. 1.

An overview of key signaling kinases (PKCs and ERK1/2) targeting transcription factors involved critical for cholesterol homeostasis. Cholesterol homeostasis is governed by 3 key transcription factors: SREBP-2, LXR, and FXR. SREBP-2 upregulates target genes involved in cholesterol biosynthesis and uptake in response to low-cellular cholesterol, whereas cholesterol catabolism and efflux are promoted through LXR in response to excess cholesterol. Bile acids activate FXR, which reduces conversion of cholesterol to bile acids by downregulating the expression of enzymes involved in bile acid synthesis, such as Cyp7a1 and Cyp8b1. It also promotes fatty acid synthesis via induction of SREBP-1c and its targets. Secretion of triglyceride-rich very low-density lipoproteins by the liver transports lipids to peripheral tissues. Bile acid-sensitive FXR reduces conversion of cholesterol to bile acids by downregulating expression of Cyp7a1 and Cyp8b1 genes. FXR also promotes the transport of bile acids to the gallbladder via bile salt export pump, multidrug resistance proteins 2 and 3. Within the intestine, FXR reduces the bile acid absorption via downregulation of the apical sodium-dependent bile acid transporter, promotes bile acid movement across the enterocytes via ileal bile acid binding protein, and promotes recycling of bile acids to the liver. FXR also promotes the release of FGF15 in mice or FGF19 in humans from the intestine. FGF15/19 travels to the liver, acting on FGF4 receptor to reduce Cyp7a1 expression and thus repress bile acid synthesis. FXR reduces lipogenesis via inhibition of SREBP-1c. Red and orange arrows indicate ERK1/2- and PKC-dependent metabolic steps, respectively. HDL, High-density lipoprotein; HDLR, HDL receptor; LDL, Low-density lipoprotein; LDLR, LDL receptor; VLDL, Very low density lipoprotein.