Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids

Abstract

The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor (FXR) and the G-protein-coupled bile acid receptor (TGR5).

Keywords: ACCII, acetyl-CoA carboxylase 2; APO, apolipoproteins; ASBT, apical sodium-dependent bile acid transporter; BSEP, bile salt export pump; Bile acids; CYP7A1, cholesterol 7α-hydroxylase; DIO2, deiodinase 2; Energy homeostasis; FAS, fatty acid synthase; FGF, fibroblast growth factor; FGFR4, fibroblast growth factor receptor 4; FOXO1, forkhead box protein O1; FXR, farnesoid X-receptor; G6Pase, glucose-6-phosphatase; GLP-1, glucagon-like polypeptide-1; HNF4α, hepatocyte nuclear factor 4 alpha; IBABP, ileal bile acid binding protein; Intestine; LDL, low density lipoprotein; Lipid metabolism; Liver; NTCP, Na+-taurocholate transporting polypeptide; OATP, organic anion transporting polypeptide; OST, organic solute transporter; PEPCK, phosphoenolpyruvate carboxykinase; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PPAR, peroxisome proliferator-activated receptor; SHP, small heterodimer partner; SREBP1c, sterol regulatory element binding protein-1c; T4, thyroid hormone; TGR5, G-protein-coupled bile acid receptor; Transporters; VLDL, very low density lipoprotein.

Graphical abstract

Figure 1

Bile acid (BA) mediated activation of FXR and TGR5 pathways in the enterohepatic circulation and systemic tissues. In the hepatocyte, bile acid activation of FXR increased SHP expression, which can decrease expression of SREBP1c and lipogenesis. Hepatic SHP activation can also lead to decreased expression of G6Pase and PEPCK, and reduced gluconeogenesis. FXR regulation of lipid metabolism and transport may involve decreasing the expression of fatty acid synthase (FAS) and apolipoproteins such as ApoAI, and inducting PPARα. FXR also controls bile acid transport by titrating the expression of NTCP (import) and BSEP (export) in the hepatocyte, and ASBT, OSTα-OSTβ, and IBABP in ileal enterocytes. FXR stimulation in the intestine increases the production of FGF15/19, which can have systemic effects on acetyl-CoA carboxylase 2 (ACCII), SREBP1c and PPAR expression in white adipose. TGR5 stimulation in the brown adipose (and skeletal muscle, not pictured) can stimulate deiodinase (DIO2) expression, which leads to increased energy expenditure and metabolic rate. TGR5 activation in the colon (not shown) can also increase release of glucagon-like polypeptide-1 (GLP-1), leading to improved glucose disposition and increased insulin sensitivity.

Figure 2

Predicted regulatory and metabolic effects of blocking ileal apical membrane (Asbt null mice) versus ileal basolateral membrane (Ostα null mice) bile acid transport. The arrows indicate the direction of predicted changes in Asbt null mice or Ostα null mice relative to wild type mice for the indicated physiological processes or pathways.