A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet
Abstract
:1. Introduction
2. Results
2.1. Fxrα1TG Mice Have Increased Expression of FXR in the Small Intestine
2.2. An n-6HFD Increases Body Weight in WT and Fxrα1TG Mice
2.3. n-6HFD and Fxrα1TG Coordinate Enterohepatic Gene Expression
2.4. An n-6HFD and Fxrα1TG Coordinate Enterohepatic Ba Homeostasis
2.5. An n-6HFD and Fxrα1TG Regulate Expression of Genes Involved in BA Homeostasis
Summary
- An n-6HFD diet augments Pparγ1 expression in the small intestine, supporting its role on fatty acid metabolism (Figure 6).
- An n-6HFD diet increases cecal CDCA and CA levels (Figure 7), and liver total BAs.
- An n-6HFD reduces cecal secondary BAs (LCA, DCA) independently of Fxrα1 transgene expression (Figure 11).
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. mRNA Analysis
4.3. Western Blot Analysis
4.4. Total Bile Acids
4.5. Liquid Chromatography and Mass Spectrometry
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
APC | Adenomatous polyposis Coli |
αMCA | α-muricholic acid |
βMCA | β-muricholic acid |
BA | Bile acid |
CA | Cholic acid |
CDCA | Chenodeoxycholic acid |
CNTL | Control diet |
CYP7A1 | Cytochrome P450 7A1 |
DCA | Deoxycholic acid |
FGF15/19 | Fibroblast growth factor 15/19 |
FGFR4 | Fibroblast growth factor receptor-4 |
FXR | Farnesoid X receptor |
FXRE | Farnesoid X receptor element |
G | Glycine conjugated |
HNF4α | Hepatocyte nuclear factor 4α |
LA | Linoleic acid |
IBABP | Ileac bile acid-binding protein |
LCA | Lithocholic acid |
MDCA | Murideoxycholic acid |
MYTG | Methionine-tyrosine-threonine-glycine |
LRH-1 | Liver-related homolog-1 |
n-6HFD | Omega-6 high-fat diet |
NAFLD | Nonalcoholic fatty liver disease |
PPARγ1−2 | Peroxisome proliferator-activated receptor-γ1 and -γ2 |
PUFA | Polyunsaturated fatty acid |
SFA | Saturated fatty acid |
SHP | Small heterodimer protein |
T | Taurine conjugated |
T-CA | Taurine-cholic acid |
T-CDCA | Taurine-chenodeoxycholic acid |
T-βMCA | Taurine-β-muricholic acid |
UDCA | Ursodeoxycholic acid |
WT | Wild type |
%E | Percent energy |
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Diet Formula | AIN-93M Purified Diet (g/kg) | CNTL (g/kg) | n-6HFD (g/kg) | |||
---|---|---|---|---|---|---|
Casein | 140.0 | 140.0 | 140.0 | |||
L-Cystine | 1.8 | 1.8 | 1.8 | |||
Corn Starch | 465.7 | 267.5 | 87.5 | |||
Maltodextrin | 155.0 | 155.0 | 155.0 | |||
Sucrose | 100.0 | 100.0 | 100.0 | |||
Soybean Oil | 40.0 | 200.0 | ||||
Palm Oil | 110.0 | |||||
Cellulose | 50.0 | 155.0 | 290.0 | |||
Mineral Mix, AIN-93M-MX (94049) | 35.0 | 35.0 | 35.0 | |||
Mineral Mix, AIN-93-VX (94047) | 10.0 | 10.0 | 10.0 | |||
Choline Bitartrate | 2.5 | 2.5 | 2.5 | |||
TBHQ, Antioxidant | 0.01 | 0.02 | 0.04 | |||
Nutrient Composition | % Weight | % Kcal | % Weight | % Kcal | % Weight | % Kcal |
Protein | 12.4 | 13.7 | 12.4 | 13.7 | 12.4 | 13.7 |
Carbohydrate | 68.3 | 75.9 | 52.8 | 58.4 | 32.3 | 35.9 |
Fat | 4.1 | 10.3 | 11.1 | 27.8 | 20.1 | 50.3 |
Energy (Kcal/g) | 3.6 | 3.6 | 3.6 |
Target | Primer Sequence |
---|---|
Fxrα1/2 | F: 5′-GGCTACGGACGAGTTTTCTCT-3′ |
R: 5′-CTCCCTGGTACCCAGTCTCA-3′ | |
Shp | F: 5′-TCCTCATGGCCTCTACCCTC-3′ |
R: 5′-TCTCCCATGATAGGGCGGAA-3′ | |
Ibabp | F: 5′-CAGGAGACGTGATTGAAAGGG-3′ |
R: 5′-GCCCCCAGAGTAAGACTGGG-3′ | |
Cyp7a1 | F: 5′-TGGGGCCTGAGTTTCATCAC-3′ |
R: 5′-CGAGAGCATGTCGAAACTTCC-3′ | |
Pparγ1 | F: 5′-GTGAGACCAACAGCCTGACG-3′ |
R: 5′-ACAGACTCGGCACTCAATGG-3′ | |
Gapdh | F: 5′-CACTTGAAGGGTGGAGCCAA-3′ |
R: 5′-AGTGATGGCATGGACTGTGG-3′ |
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Wren, S.N.; Donovan, M.G.; Selmin, O.I.; Doetschman, T.C.; Romagnolo, D.F. A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet. Int. J. Mol. Sci. 2020, 21, 7829. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217829
Wren SN, Donovan MG, Selmin OI, Doetschman TC, Romagnolo DF. A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet. International Journal of Molecular Sciences. 2020; 21(21):7829. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217829
Chicago/Turabian StyleWren, Spencer N., Micah G. Donovan, Ornella I. Selmin, Tom C. Doetschman, and Donato F. Romagnolo. 2020. "A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet" International Journal of Molecular Sciences 21, no. 21: 7829. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217829