Abstract
Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. Bile acids are ligands that can bind to several receptors, including the nuclear receptor farnesoid X receptor (FXR) in ileal enterocytes. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acid-related disorders.
Highlights
Bile acids are physiological detergent molecules synthesized from cholesterol that were once thought to primarily function in the intestinal tract to solubilize and facilitate absorption of fats, steroids, and fat-soluble vitamins
farnesoid X receptor (FXR) forms a heterodimer with retinoid X receptor (RXR) which binds to an inverted repeat (IR)-1 element on the gene promoter for BSEP or OSTa-OSTb to induce the transporter production in a positive feed forward manner [26]
Therapies aimed at inhibiting fibroblast growth factor 19 (FGF19) and FGFR4 are in various phases of development, including clinical trials for several malignancies including hepatocellular carcinoma (HCC) [84]
Summary
The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling. Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acidrelated disorders
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