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...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/21/7829 |
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| author | Spencer N. Wren Micah G. Donovan Ornella I. Selmin Tom C. Doetschman Donato F. Romagnolo |
| author_facet | Spencer N. Wren Micah G. Donovan Ornella I. Selmin Tom C. Doetschman Donato F. Romagnolo |
| author_sort | Spencer N. Wren |
| collection | DOAJ |
| description | 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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| spelling | doaj.art-ba4acf31c27242cf83c3300d5bad1f8e2023-11-20T18:07:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012121782910.3390/ijms21217829A <i>Villin</i>-Driven <i>Fxr</i> Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an <i>n</i>-6-Enriched High-Fat DietSpencer N. Wren0Micah G. Donovan1Ornella I. Selmin2Tom C. Doetschman3Donato F. Romagnolo4Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USAInterdisciplinary Cancer Biology Graduate Program, The University of Arizona, Tucson, AZ 85724, USADepartment of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USADepartment of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85724, USADepartment of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USAA 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.https://www.mdpi.com/1422-0067/21/21/7829farnesoid X receptorbile acidshigh-fat dietsoybean oil<i>n</i>-6linoleic acid |
| spellingShingle | Spencer N. Wren Micah G. Donovan Ornella I. Selmin Tom C. Doetschman Donato F. Romagnolo 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 International Journal of Molecular Sciences farnesoid X receptor bile acids high-fat diet soybean oil <i>n</i>-6 linoleic acid |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | farnesoid X receptor bile acids high-fat diet soybean oil <i>n</i>-6 linoleic acid |
| url | https://www.mdpi.com/1422-0067/21/21/7829 |
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