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Intestinal Absorption of Bile Acids in Health and Disease

Alexander L. Ticho, Pooja Malhotra, Pradeep K. Dudeja, Ravinder K. Gill, Waddah A. Alrefai

10.1002/cphy.c190007

Source: Volume 10, Issue 1, January 2020

Published online: December 2019

Full Article on Wiley Online Library



Abstract

The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein‐coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid‐induced ileal hormone FGF15/19 is implicated in bile acid‐induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid‐related disorders. Published 2020. Compr Physiol 10:21‐56, 2020.

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Figure 1. Figure 1. Structure of common mammalian bile acids. (A) The structure of bile acids can be visualized by orienting the plane of the molecule perpendicular to the page, such that α‐hydroxyl moieties are on the right side of the steroid nucleus and β‐hydroxyl moieties are on the left side. This can be represented by a block diagram, where the rectangles represent the steroid nucleus with selected carbon atoms labeled by number and the red circles represent the hydroxyl group. (B) Structures of primary (gray) and secondary (green) bile acids. Bacterial production of secondary bile acids occurs via the reactions depicted by black arrows. Muricholic acids and their derivatives, which are predominantly found in rodents, are shown in the yellow box.
Figure 2. Figure 2. Enterohepatic circulation of bile acids. Bile acids (BAs) are synthesized from cholesterol in the liver via the rate‐limiting enzyme CYP7A1 and secreted into the bile duct by the bile salt export pump (BSEP). These BAs are then deposited into the small intestine, where they emulsify lipids and serve as signaling molecules. Luminal BAs are taken up into ileal enterocytes by the apical sodium‐dependent bile acid transporter (ASBT) and exported into the portal blood by the organic solute transporter α/β heterodimer (OSTα/β). These BAs return to the liver, where they are taken into hepatocytes (mainly in the periportal region of the hepatic acinus) by the Na+‐taurocholate cotransporting polypeptide (NTCP) and resecreted by BSEP. Within the enterocyte, BAs activate the farnesoid X receptor (FXR), which induces fibroblast growth factor 15/19 (FGF15/19) expression and secretion into the portal blood. FGF15/19 travels to the liver, where it binds to the FGF receptor 4 (FGFR4)/β‐klotho (β‐kl) complex. Activation of this complex reduces CYP7A1 expression, thus decreasing bile acid synthesis.
Figure 3. Figure 3. Bile acid transport and signaling in the ileum. Luminal BAs are taken up into ileal enterocytes by the apical sodium‐dependent bile acid transporter (ASBT), where they are bound by the ileal bile acid‐binding protein (IBABP) and transported to the basolateral membrane. BAs are exported basolaterally by the organic solute transporter α/β heterodimer (OSTα/β) and returned to the liver. Intracellular BAs activate the farnesoid X receptor (FXR), which heterodimerizes with the retinoid X receptor (RXR) and translocates to the nucleus. There, FXR transactivates fibroblast growth factor 15/19 (FGF15/19), OSTα/β, and the small heterodimeric partner (SHP). ASBT expression is negatively regulated by SHP within the cell and by an autocrine/paracrine function of FGF15/19, which binds to the FGF receptor 4 (FGFR4)/β‐klotho (β‐kl) complex and activates signaling processes that repress ASBT. Bile acid diarrhea can be caused by disruptions in these processes. Notably, reduced FGF19 disrupts the negative feedback of bile acid synthesis resulting in bile acid overproduction, while reduced ASBT impairs bile acid absorption.
Figure 4. Figure 4. Topology of ASBT. A cartoon of the 7‐transmembrane ASBT topology with transmembrane (TM), extracellular loop (EL), and intracellular loop (IL) domains. Sites of posttranslational modifications (glycosylation and phosphorylation), clinically relevant missense mutations, and GxxxG motifs are shown.
Figure 5. Figure 5. Acute, posttranslational regulation of ASBT. Functional ASBT, which transports two Na+ ions along with one bile acid, is present in lipid rafts. Movement of ASBT out of rafts, either by the green tea catechin (−)‐epigallocatechin‐3‐gallate (EGCG) or methyl‐β‐cyclodextrin (MβCD), decreases ASBT function. Activation of protein kinase C ζ (PKCζ) by phorbol 12‐myristate 13‐acetate (PMA) results in endocytosis and reduced function of ASBT. Similarly, activation of protein tyrosine phosphatases (PTP) by enteropathogenic Escherichia coli (EPEC) causes endocytosis of ASBT.


Figure 1. Structure of common mammalian bile acids. (A) The structure of bile acids can be visualized by orienting the plane of the molecule perpendicular to the page, such that α‐hydroxyl moieties are on the right side of the steroid nucleus and β‐hydroxyl moieties are on the left side. This can be represented by a block diagram, where the rectangles represent the steroid nucleus with selected carbon atoms labeled by number and the red circles represent the hydroxyl group. (B) Structures of primary (gray) and secondary (green) bile acids. Bacterial production of secondary bile acids occurs via the reactions depicted by black arrows. Muricholic acids and their derivatives, which are predominantly found in rodents, are shown in the yellow box.


Figure 2. Enterohepatic circulation of bile acids. Bile acids (BAs) are synthesized from cholesterol in the liver via the rate‐limiting enzyme CYP7A1 and secreted into the bile duct by the bile salt export pump (BSEP). These BAs are then deposited into the small intestine, where they emulsify lipids and serve as signaling molecules. Luminal BAs are taken up into ileal enterocytes by the apical sodium‐dependent bile acid transporter (ASBT) and exported into the portal blood by the organic solute transporter α/β heterodimer (OSTα/β). These BAs return to the liver, where they are taken into hepatocytes (mainly in the periportal region of the hepatic acinus) by the Na+‐taurocholate cotransporting polypeptide (NTCP) and resecreted by BSEP. Within the enterocyte, BAs activate the farnesoid X receptor (FXR), which induces fibroblast growth factor 15/19 (FGF15/19) expression and secretion into the portal blood. FGF15/19 travels to the liver, where it binds to the FGF receptor 4 (FGFR4)/β‐klotho (β‐kl) complex. Activation of this complex reduces CYP7A1 expression, thus decreasing bile acid synthesis.


Figure 3. Bile acid transport and signaling in the ileum. Luminal BAs are taken up into ileal enterocytes by the apical sodium‐dependent bile acid transporter (ASBT), where they are bound by the ileal bile acid‐binding protein (IBABP) and transported to the basolateral membrane. BAs are exported basolaterally by the organic solute transporter α/β heterodimer (OSTα/β) and returned to the liver. Intracellular BAs activate the farnesoid X receptor (FXR), which heterodimerizes with the retinoid X receptor (RXR) and translocates to the nucleus. There, FXR transactivates fibroblast growth factor 15/19 (FGF15/19), OSTα/β, and the small heterodimeric partner (SHP). ASBT expression is negatively regulated by SHP within the cell and by an autocrine/paracrine function of FGF15/19, which binds to the FGF receptor 4 (FGFR4)/β‐klotho (β‐kl) complex and activates signaling processes that repress ASBT. Bile acid diarrhea can be caused by disruptions in these processes. Notably, reduced FGF19 disrupts the negative feedback of bile acid synthesis resulting in bile acid overproduction, while reduced ASBT impairs bile acid absorption.


Figure 4. Topology of ASBT. A cartoon of the 7‐transmembrane ASBT topology with transmembrane (TM), extracellular loop (EL), and intracellular loop (IL) domains. Sites of posttranslational modifications (glycosylation and phosphorylation), clinically relevant missense mutations, and GxxxG motifs are shown.


Figure 5. Acute, posttranslational regulation of ASBT. Functional ASBT, which transports two Na+ ions along with one bile acid, is present in lipid rafts. Movement of ASBT out of rafts, either by the green tea catechin (−)‐epigallocatechin‐3‐gallate (EGCG) or methyl‐β‐cyclodextrin (MβCD), decreases ASBT function. Activation of protein kinase C ζ (PKCζ) by phorbol 12‐myristate 13‐acetate (PMA) results in endocytosis and reduced function of ASBT. Similarly, activation of protein tyrosine phosphatases (PTP) by enteropathogenic Escherichia coli (EPEC) causes endocytosis of ASBT.
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Teaching Material

Alexander L. Ticho, Pooja Malhotra, Pradeep K. Dudeja, Ravinder K. Gill, Waddah A. Alrefai. Intestinal absorption of bile acids in health and disease. Compr Physiol 10 : 2020, 21-56.

Didactic Synopsis

Major Teaching Points:

-The enterohepatic circulation of bile acids entails: synthesis and secretion from the liver, re-absorption from the intestine, re-circulation back to liver via the portal blood, and re-secretion from the liver.

-Bile acids are efficiently reabsorbed in the intestine with only 5% lost in the feces.

-Bile acid absorption is critical for the negative feedback inhibition of their synthesis in the liver via the secretion of ileal fibroblast Growth Factor FGF19/15 hormone.

-Bile acids are crucial for lipid digestion and absorption due to their roles as fat solubilizers. Bile acids also activate specific receptors and signaling pathways to modulate a number of hepatic and intestinal functions and exert systemic effects such as increasing energy expenditure and improving insulin sensitivity.

-Disturbances in the enterohepatic circulation of bile acids contribute the pathophysiology of hepatic and intestinal disorders such as cholestatic liver diseases and inflammatory bowel disorders.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching points: The structure of different types of bile acids can be depicted by a schematic representation of these molecules demonstrating the location and orientation of the hyrodxyl groups relevant to the plain of the steroid ring. The primary bile acids in mice and humans are directly synthesized in the liver. Secondary bile acids are the products of de-hydroxylation and/or OH-epimerization of primary bile acids mediated by bacterial enzymes from gut microbiota.

Figure 2. Teaching points: Bile acids are conserved in the enterohepatic circulation and only 5% of total bile acids is lost in feces. The efficiency of bile acid absorption influences the hepatic synthesis of those molecules via inducing the secretion of the ileal hormone FGF19 (FGF15 in rodents) that circulates to the liver to inhibit CYP7A1-mediated bile acid synthesis. Blocking bile acid absorption decreases FGF19-mediated negative feedback and, hence, promotes bile acid synthesis from cholesterol. Therefore, blockers of bile acid absorption could be used for the treatment of hypercholesterolemia.

Figure 3. Teaching points: The increase in the amounts of bile acids in the colonic lumen stimulates the secretion of electrolytes and water leading to diarrhea. Bile acid diarrhea may occur due to bile acid malabsorption as a result of a decrease in the expression and/or function of the ileal Apical Sodium-Dependent Bile acid Transporter (ASBT). A decrease in FGF19 expression also leads to an increase in the hepatic production of bile acids and subsequent overload in the intestine causing diarrhea.

Figure 4. Teaching points: The ileal bile acid transporter ASBT is subject to post-translational modifications including N-glycosylation on the first extracellular loop and serine-threonine phosphorylation on the intracellular c-terminal of the protein. These post-translational modifications modulate the function of ASBT. Also, certain mutations have been identified that cause impaired ASBT function.

Figure 5. Teaching points: ASBT function is crucial for the intestinal reclamation of bile acids. ASBT is rapidly regulated by different mechanisms. The disruption of lipid rafts of plasma membrane by dietary compounds such as the green tea catechin EGCG decreases ASBT function. ASBT membrane expression is decreased by endocytosis in response to activation of protein kinase c-zeta. The activation of protein tyrosine phosphatases in response to infection with enteric microbes such as EPEC decreases ASBT function and expression on the plasma membrane.

 


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Article Title: Intestinal Absorption of Bile Acids in Health and Disease
 

How to Cite

Alexander L. Ticho, Pooja Malhotra, Pradeep K. Dudeja, Ravinder K. Gill, Waddah A. Alrefai. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019, 10: 21-56. doi: 10.1002/cphy.c190007