A <i>Villin</i>-Driven <i>Fxr</i> Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an <i>n</i>-6-Enriched High-Fat Diet
A diet high in <i>n</i>-6 polyunsaturated fatty acids (PUFAs) may contribute to inflammation and tissue damage associated with obesity and pathologies of the colon and liver. One contributing factor may be dysregulation by <i>n</i>-6 fatty acids of enterohepatic bile acid (BA...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/21/7829 |
| Summary: | A diet high in <i>n</i>-6 polyunsaturated fatty acids (PUFAs) may contribute to inflammation and tissue damage associated with obesity and pathologies of the colon and liver. One contributing factor may be dysregulation by <i>n</i>-6 fatty acids of enterohepatic bile acid (BA) metabolism. The farnesoid X receptor (FXR) is a nuclear receptor that regulates BA homeostasis in the liver and intestine. This study aims to compare the effects on FXR regulation and BA metabolism of a palm oil-based diet providing 28% energy (28%E) from fat and low <i>n</i>-6 linoleic acid (LA, 2.5%E) (CNTL) with those of a soybean oil-based diet providing 50%E from fat and high (28%E) in LA (<i>n</i>-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the <i>Fxrα1</i> isoform under the control of the intestine-specific <i>Villin</i> promoter (<i>Fxrα1<sup>TG</sup></i>) were fed the CNTL or <i>n</i>-6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the <i>n</i>-6HFD supports higher weight gain in both WT and <i>Fxrα<sup>TG</sup></i> littermates; increases the expression of <i>Fxr</i>α<i>1/2</i>, and peroxisome proliferator-activated receptor-γ<i>1</i> (<i>Pparγ1</i>) in the small intestine, <i>Fxrα1/2</i> in the colon, and cytochrome P4507A1 (<i>Cyp7a1</i>) and small heterodimer protein (<i>Shp</i>) in the liver; and augments the levels of total BA in the liver, and primary chenodeoxycholic (CDCA), cholic (CA), and β-muricholic (βMCA) acid in the cecum. Intestinal overexpression of the <i>Fxra1<sup>TG</sup></i> augments expression of <i>Shp</i> and ileal bile acid-binding protein (<i>Ibabp)</i> in the small intestine and <i>Ibabp</i> in the proximal colon. Conversely, it antagonizes <i>n</i>-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of <i>Cyp7a1</i>; and expression of <i>Pparγ</i> in the small intestine. We conclude that intestinal <i>Fxrα1</i> overexpression represses hepatic de novo BA synthesis and protects against <i>n</i>-6HFD-induced accumulation of human-specific primary bile acids in the cecum. |
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| ISSN: | 1661-6596 1422-0067 |