Farnesoid X Receptor as a homeostat for hepatic nutrient metabolism, proliferation and intestinal inflammation: Novel insights into mechanisms of regulation

Abstract

Our body hosts several molecules that function as hormones to regulate metabolism in the liver. Bile acids (BAs) are molecules produced by the liver and stored in the gall bladder. After eating a meal, BAs are secreted in the intestine, where they help the digestion of fats and vitamins. Subsequently, most BAs are re-absorbed in the intestine and recycled to the liver, where they function as hormones to regulate hepatic metabolism. Meanwhile, glucose, triacylglycerols and amino acids are absorbed in the intestine and reach the liver. The fate of BAs and nutrients in the liver is tightly connected through the function of one protein, the Farnesoid X Receptor (FXR). As explained in Chapter 2, FXR acts as a ‘homeostat’ of liver metabolism, meaning a gatekeeper of metabolic homeostasis, since it senses environmental changes (fed state) and drives transcriptional programs that inhibit BA synthesis, and redistribute the energy substrates. In Chapter 3, we report a novel function of FXR as a metabolic regulator of amino acids. In mouse liver tissue and isolated liver cells, FXR activation resulted in upregulation of proteins involved in amino acid degradation, ureagenesis and glutamine synthesis. The impact of our findings is therefore substantial, as it might be possible to prevent the accumulation of toxic ammonium in patients with liver disease, by activating FXR in these patients. Metabolism relates closely to cell proliferation and inflammation, since you need to adapt your metabolic needs in order to grow or defend yourself from pathogens or injury. In the fed state, FXR activates FGF19 in the intestine. FGF19 is a hormone-like regulating hepatic metabolism. In Chapter 4, we show that FGF19 targets both metabolism and cell proliferation, thereby FGF19-based therapeutics may have tumorigenic risks. The combination of environmental factors (e.g. diet), dysregulation of immune response and damage in the intestinal epithelial barrier function, may trigger inflammatory bowel disease (IBD) in genetically predisposed individuals. FXR activation attenuates the severity of colitis in murine models of IBD. In Chapter 5, we show that FXR activation decreases the levels of anti-inflammatory cytokines in plasma, and counteracts the depletion in splenic dendritic cells (DC) and the increase in Tregs, both occurring as a consequence of colitis. We propose that FXR activation may induce DC retention in the spleen and affect the chemotactic environment in the colon. The central role of FXR in various aspects of metabolism and inflammation makes FXR an attractive drug target in cholestatic diseases, non-alcoholic steatohepatitis (NASH), IBD, and metabolic syndrome, but current compounds act as full agonists of FXR that may have undesired biological actions.Coregulatory proteins are eligible targets for pharmacological modulation of selective FXR functions.In Chapter 6, we identify HOXA9 and NSD1 as proteins which bind and regulate FXR in liver cells. In conclusion, active FXR protects against liver ammonium toxicity and fat accumulation and intestinal inflammation. Elucidation of FXR mechanistic actions is necessary the rational design of a new generation of FXR drugs, selectively activating or repressing specific FXR functions.