Bile acids
Bile acids (BA) are the components of human bile and have an integral role in health, through the absorption of lipophilic nutrients and vitamins. Bile acids are produced by hepatocytes as ‘primary’ BA but undergo further metabolism to ‘secondary’ BA by commensal bacteria during their passage through the gut, prior to their absorption and return to the liver. The elucidation of the pathways governing BA recycling between the gut and the liver (enterohepatic circulation) as well as the identi?cation of BA-speci?c receptors in a multitude of cell-types and different tissues have underlined their role in health and disease mainly in relation to metabolic and liver diseases.BA synthesis is mainly by two differential pathways: The “classic (or neutral) pathway” and the “alternative (or acidic) pathway”. In the classic pathway, hydroxylation at C7? position which is the first step is catalyzed by the enzyme cholesterol7?-hydroxylase (CYP7A1). In the alternate pathway, first hydroxylation at C27 position is carried out by the enzyme sterol-27?-hydroxylase (CYP27A1). Generally the classic pathway is mainly more important pathway than the alternative pathway since it is responsible for maintaining cholesterol homeostasis.
The BAs activates intestinal FXR which causes an increased expression of fibroblast growth factor (FGF)-15 in rodents and FGF-19 in humans. Bile acids are absorbed in the ileum activates FXR so as to induce production of FGF-15/19. FGF-15/19 passes through the portal vein to the hepatocytes and couples with FGF receptor 4 (FGFR4) which inturn induces receptor dimerization, autophosphorylation, and c-Jun N-terminal kinase pathway activation resulting in the repression of CYP7A1 transcription. TGR5/M-BAR, . a 2nd BA receptor also contributes for the regulation of Bile acid homeostasis. Phosphoenolpyruvate carboxykinase(PEPCK),which is the rate limiting enzyme of gluconeogenesis is suppressed by Bile acids. BAs repress enzymes, glucose 6-Phosphatase and fructose 1,6-bisphosphatase . BAs stimulate incretins, such as glucagon like peptide-1 which promotes insulin secretion by binding to the GLP-1 receptor in pancreatic ? cells.The target of FXR,SHP, suppressed up regulation of sterol regulatory element binding protein-1c(SREBP-1c) to reduce TG synthesis(fig 1).
Figure 1A. Farnesoid X receptor-dependent metabolic regulation in the liver. B. TGR5/M-BAR-dependent metabolic regulation (Ref-1)
Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Stimulation of FXR supresses autophagy in the liver. At the promoter regions of autophagic genes FXR and PPAR? competitively bind and show effects on transcription mainly based on nutrional conditions. Basically in liver, under fasted conditions PPAR? activation promotes autophagic lipolysis. FXR stimulation caused by feeding disrupts the functional CREB-CRTC2 complex and downregulates autophagy(fig 2).
Figure 2. Farnesoid X receptor role in Autophagy regulation (Ref-1)
Figure 3. Intestinal FXR activity on conflicting mechanisms of metabolic regulation (Ref-1)
Induction of FGF-15/19 expression by intestinal FXR activation affects glucose and energy homeostasis. Increased ?-oxidation in the liver by overexpression of FGF-19. FXR activation by administration of fexaramine, an FXR agonist, improved insulin resistance and obesity by inducing FGF-15 which inturn changes BA composition in serum readily stimulates systemic TGR5. T-?-MCA is an FXR antagonist, and microbiota affect bile acid homeostasis via the inhibition of intestinal FXR signalling by change in BA composition which inturn improves lipid and glucose metabolism. Increased T- ?-MCA leads to reduced intestinal FXR activation and decreased serum ceramide levels through repression of ceramide synthesis which in turn downregulates hepatic SREBP-1c leading to improvement in NAFLD and obesity. Intestinal FXR deactivation also improve glucose and lipid metabolism. BABR(Bile acid binding resin) can decrease blood glucose levels only in high glucose situations as it induces GLP-1 secretion via activation of TGR5(Fig 3).
