Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.
Highlights
Bile acids (BA) are amphipathic molecules made from cholesterol in the liver in the pericentral hepatocytes
The regulation of energy homeostasis [1,48,49,50] relies on increased host energy expenditure [43,56,91,92,93] in skeletal muscle and brown adipose tissue, where G protein-coupled bile acid receptor 1 (GPBAR-1) stimulation results in local activation of the type II iodothyronine deiodinase (DIO2)
GPBAR-1 activation has a stronger effect on ductular component of bile secretion, i.e., on the regulation of CFTR-dependent Cl- secretion in human gallbladder [104] and other epithelial cells [107,108], as well as on biliary pH regulation after partial hepatectomy in mice [47]
Summary
Bile acids (BA) are amphipathic molecules made from cholesterol in the liver in the pericentral hepatocytes. The alternative “acidic” pathway is mitochondrial and BA in the liver undergo conjugation with amino acids, glycine or taurine (ratio of 3:1), via N-acyl contributes to 10–25% of total BA pool [1,7] with the rate-limiting enzyme cholesterol 27αamidation at carbon 24 of the aliphatic side chain [10] and active biliary secretion. BA pool (~3 g, mainly in the liver and intestine), active (80%) BA reabsorption at the terminal ileum and key events the enterohepatic circulation of BA appear in Figure passiveThe diffusion (15%)contributing in the colon,todaily recirculation within the axis which includes liver 2secretion, According to this scenario, most in the pool stay in the enterohepatic circulation due to the intestinal flow and reabsorption, portal blood flow, liver uptake (4–12 cycles per day), and dynamic following essential steps: primary synthesis (0.2–0.6 formation total and increase of the BA pool by 4–12 folds BA (=12–36 g/day). BAprotein uptake occurs across the apical sodium dependent acid transporter (ASBT), the intracellular (MDR1), and stored in the gallbladder upon bile neurohormonal-mediated contraction.
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