Bile acids as regulators of hepatic lipid and glucose metabolism

Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, bile acids (BA) also act as metabolically active signaling molecules. The flux of reabsorbed BA undergoing enterohepatic circulation, arriving in the liver with the co-absorbed nutrients (e.g. glucose, lipids), provides a signal that coordinates hepatic triglyceride (TG), glucose and energy homeostasis. As signaling molecules with systemic endocrine functions, BA can activate protein kinases A and C as well as mitogen-activated protein kinase pathways. Additionally, they are ligands for a G-protein-coupled BA receptor (TGR5/Gpbar-1) and activate nuclear receptors such as farnesoid X receptor (FXR; NR1H4). FXR and its downstream targets play a key role in the control of hepatic de novo lipogenesis, very-low-density lipoprotein-TG export and plasma TG turnover. BA-activated FXR and signal transduction pathways are also involved in the regulation of hepatic gluconeogenesis, glycogen synthesis and insulin sensitivity. Via TGR5, BA are able to stimulate glucagon-like peptide-1 secretion in the small intestine and energy expenditure in brown adipose tissue and skeletal muscle. Dysregulation of BA transport and impaired BA receptor signaling may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thus, BA transport and BA-controlled nuclear receptors and signaling pathways are promising drug targets for treatment of NAFLD. As such, FXR and/or TGR5 ligands have shown promising results in animal models of NAFLD and clinical pilot studies. Despite being a poor FXR and TGR5 ligand, ursodeoxycholic acid (UDCA) improves hepatic ER stress and insulin sensitivity. Notably, norUDCA, a side chain-shortened homologue of UDCA, improves fatty liver and atherosclerosis in Western diet-fed ApoE(-/-) mice. Collectively, these findings suggest that BA and targeting their receptor/signaling pathways may represent a promising approach to treat NAFLD and closely linked disorders such as obesity, diabetes, dyslipidemia and arteriosclerosis.