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Review
. 2019 May 1;1865(5):895-911.
doi: 10.1016/j.bbadis.2018.05.011. Epub 2018 May 18.

Animal models to study bile acid metabolism

Jianing Li  1 , Paul A Dawson  2
Affiliations
Review

Animal models to study bile acid metabolism

"VSports手机版" Jianing Li et al. Biochim Biophys Acta Mol Basis Dis. .

Abstract (V体育2025版)

The use of animal models, particularly genetically modified mice, continues to play a critical role in studying the relationship between bile acid metabolism and human liver disease. Over the past 20 years, these studies have been instrumental in elucidating the major pathways responsible for bile acid biosynthesis and enterohepatic cycling, and the molecular mechanisms regulating those pathways. This work also revealed bile acid differences between species, particularly in the composition, physicochemical properties, and signaling potential of the bile acid pool. These species differences may limit the ability to translate findings regarding bile acid-related disease processes from mice to humans VSports手机版. In this review, we focus primarily on mouse models and also briefly discuss dietary or surgical models commonly used to study the basic mechanisms underlying bile acid metabolism. Important phenotypic species differences in bile acid metabolism between mice and humans are highlighted. .

Keywords: Enterohepatic circulation; Enzyme; Intestine; Liver; Mouse model; Transporter. V体育安卓版.

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Figures

Figure 1
Figure 1. Bile acids present in humans and mice
(A) Structure and sites of hydroxylation on the steroid nucleus for bile acid species found in humans and mice. Hydroxyl groups that are oriented in the α-orientation are located below the steroid nucleus and are axial to the plane of the steroid nucleus. Hydroxyl groups that are in the β-orientation are located above the steroid nucleus and are equatorial to the plane of the steroid nucleus. (B) Relative biliary bile acid composition in humans and in conventionalized and germ-free mice (modified from Wahlström et al; [48]).
Figure 2
Figure 2. Bile acid synthesis and metabolism in humans and mice
Major pathways for bile acid synthesis and metabolism in humans and mice. (A) The classical pathway for bile acid synthesis begins with cholesterol 7α-hydroxylase (CYP7A1) and intermediates synthesized via this pathway are substrates for the sterol 12α-hydroxylase (CYP8B1), which generates CA. The alternative pathway begins with sterol 27-hydroxylase (CYP27A1) and generates predominantly CDCA. In mice, CDCA and UDCA undergo 6β-hydroxylation by the cytochrome P450, Cyp2c70 to generate αMCA and βMCA. (B) In humans, bile acids in the liver are conjugated (n-acyl-amidated) with glycine (G) or taurine (T), whereas mice use almost exclusively taurine. (C) Primary bile acids are biotransformed by the gut microbiota. These reactions include deconjugation, which is catalyzed by bile salt hydrolases (BSH), epimerization to change the orientation of the hydroxyl groups on the steroid nucleus of the bile acids, and 7-dehydroxylation. (D) After returning to the liver, conjugated DCA can be rehydroxylated at the C-7 position to regenerate conjugated CA. This reaction occurs in mice and other species but is apparently absent in humans. (E) Bile acids undergo Phase 1 and Phase 2 metabolism, including additional hydroxylation, sulfation (sulfonation), and glucuronidation. In humans, sulfation of bile acids such as LCA is a primary pathway for their detoxification, whereas in mice hydroxylation plays a dominant role. The locations of these additional modifications to the bile acid structure are indicated.
Figure 3
Figure 3. Enterohepatic circulation of bile acids showing the major transport proteins
(Left panel) After their synthesis, conjugated monovalent bile acids are secreted into bile canaliculi by the bile salt export pump (BSEP), whereas modified (sulfated, glucuronidated and polyhydroxylated) bile acids can be secreted by the canalicular transporters, MRP2 and MDR1. Alternatively, monovalent or modified bile acids can be effluxed across the basolateral (sinusoidal) membrane of the hepatocyte by OSTα-OSTβ, MRP3, MRP4, and possibly other transporters as a mechanism to protect the hepatocytes from bile acid overload. A fraction of the bile acids secreted into bile undergo “Cholehepatic Shunting” (green dotted line), whereby the bile acids are prematurely absorbed in the biliary tract and returned directly to the liver. Unconjugated bile acids or bile acid analogs such as norUDCA undergo passive absorption, whereas conjugated bile acids can be absorbed by cholangiocytes via the ASBT and exported by OSTα-OSTβ for return to the hepatocyte in the periductular circulation. Ultimately, the bile acids secreted into bile move through the biliary tract, empty into the intestinal lumen, and are passively absorbed along the length of the intestine and actively absorbed in the ileum. The bile acids are then carried back to the liver in the portal circulation for hepatocellular reuptake and resecretion into bile (red dotted line). (Right panel) The transporters that maintain the enterohepatic circulation of bile acids are largely conserved between humans in mice. In mice but not humans, members of the Oatp family appear to play an important secondary role in hepatic uptake of conjugated bile acids.
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