Of mice and men: murine bile acids explain species differences in the regulation of bile acid and cholesterol metabolism

Abstract

Compared with humans, rodents have higher synthesis of cholesterol and bile acids (BAs) and faster clearance and lower levels of serum LDL-cholesterol. Paradoxically, they increase BA synthesis in response to bile duct ligation (BDL). Another difference is the production of hydrophilic 6-hydroxylated muricholic acids (MCAs), which may antagonize the activation of FXRs, in rodents versus humans. We hypothesized that the presence of MCAs is key for many of these metabolic differences between mice and humans. We thus studied the effects of genetic deletion of the Cyp2c70 gene, previously proposed to control MCA formation. Compared with WT animals, KO mice created using the CRISPR/Cas9 system completely lacked MCAs, and displayed >50% reductions in BA and cholesterol synthesis and hepatic LDL receptors, leading to a marked increase in serum LDL-cholesterol. The doubling of BA synthesis following BDL in WT animals was abolished in KO mice, despite extinguished intestinal fibroblast growth factor (Fgf)15 expression in both groups. Accumulation of cholesterol-enriched particles (“Lp-X”) in serum was almost eliminated in KO mice. Livers of KO mice were increased 18% in weight, and serum markers of liver function indicated liver damage. The human-like phenotype of BA metabolism in KO mice could not be fully explained by the activation of FXR-mediated changes. In conclusion, the presence of MCAs is critical for many of the known metabolic differences between mice and humans. The Cyp2c70-KO mouse should be useful in studies exploring potential therapeutic targets for human disease.

Bile Acid Signaling in Inflammatory Bowel Diseases

“…In rodents, there are additional bile acids, the α-and β-muricholic acids (MCA), generated in the liver from CDCA [19,20]. These bile acids represent the product of specific murine gene, Cyp2c70, which is absent in human, and as such Cyp2c70 −/− mice present a bile "humanized" bile acid profile [20][21][22]. Accordingly, the T conjugated of α-and β-MCA are primary bile acids in mice, while ω-MCA, generated from the two MCAs in the intestine, is a secondary bile acid.…”

The bile acid activated receptors GPBAR1 and FXR exert antagonistic effects on autophagy

“…The Cyp2c70, Cytochrome P450 family 2 subfamily c polypeptide 70, has been identified has the gene responsible for MCAs generation in rodents. [47][48][49][50] Cyp2c70 catalyzes the production of βMCA from CDCA by a two-step reaction involving first the 6β-hydroxylation of CDCA, producing α-MCA, followed by epimerization of the C7 hydroxyl group from the α to the β orientation, which generates β-MCA, In the present study, we have also shown that the liver expression of Cyp2c70 is severely blunted in Gpbar1 −/− mice, highlighting a putative regulatory mechanism for GPBAR1 on this gene. [47][48][49][50] Importantly, we have also shown that BAR501, a GPBAR1 ligand, and BAR704, a FXR ligand, both increase the liver expression of Cyp2c70 in wild-type mice ( Figure 5B), highlighting a potential role of the two receptors in regulating MCAs synthesis.…”

“…To prove this concept, we have examined the liver expression of several FXR-regulated genes 46 and found that Shp, a FXR target gene, was significantly upregulated by fasting Gpbar1 −/− mice, while Cyp27a1, which mediates the first and limiting step in the alternative pathway of bile acid synthesis, that is mainly involved in generating CDCA, the precursor of α-and β-MCA acid, was downregulated ( Figure 1E). Furthermore, Gpbar1 −/− mice exposed to fasting were characterized by a dramatically reduction in the expression of Cyp2c70, which, in mice, is responsible for the synthesis of MCAs from CDCA [47][48][49][50] ( Figure 1E). Together, these results supported the notion that Gpbar1 gene ablation causes a dysregulated FXR signaling in the liver.…”

Role of Nrf2 and Its Activators in Cardiocerebral Vascular Disease

“…In addition, experimental animals and humans have very different physiological indicators and disease tolerance, which may lead to incorrect conclusions. For example, mice and humans regulate bile acid and cholesterol metabolism differently [ 187 ], and human atherosclerotic plaques are more likely to rupture than those of mice [ 188 ]. These differences may lead to changes in the role of Nrf2 in human CCVD.…”