@article{a26fe4213dc149beac2aac7720a477b6,
title = "A villin-driven FXR transgene modulates enterohepatic bile acid homeostasis and response to an N-6-enriched high-fat diet",
abstract = "A diet high in n-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 n-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 n-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 (n-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the Fxrα1 isoform under the control of the intestine-specific Villin promoter (Fxrα1TG) were fed the CNTL or n-6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the n-6HFD supports higher weight gain in both WT and FxrαTG littermates; increases the expression of Fxrα1/2, and peroxisome proliferator-activated receptor-γ1 (Pparγ1) in the small intestine, Fxrα1/2 in the colon, and cytochrome P4507A1 (Cyp7a1) and small heterodimer protein (Shp) 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 Fxra1TG augments expression of Shp and ileal bile acid-binding protein (Ibabp) in the small intestine and Ibabp in the proximal colon. Conversely, it antagonizes n-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of Cyp7a1; and expression of Pparγ in the small intestine. We conclude that intestinal Fxrα1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of human-specific primary bile acids in the cecum.",
keywords = "Bile acids, Farnesoid X receptor, High-fat diet, Linoleic acid, N-6, Soybean oil",
author = "Wren, {Spencer N.} and Donovan, {Micah G.} and Selmin, {Ornella I.} and Doetschman, {Tom C.} and Romagnolo, {Donato F.}",
note = "Funding Information: This work was supported by a grant from USDA-NIFA, GRANT12445471; USDA-NIFA Multistate ARZT-1370460-R23-155; The University of Arizona Cancer Center Support Grant P30CA23074; and the Cancer Biology Training Grant T32CA009213. The authors wish to acknowledge the contribution of Teodora Georgieva, Genetically Engineered Mouse Models (GEMM) Core, The University of Arizona for cloning of the FXRα1 construct; Tama Taylor-Doyle (GEMM) for care of animal colonies; Gillian Paine-Murrieta, Experimental Mouse Shared Resources, The University of Arizona Cancer Center for assistance with animal surgeries and tissue collection; and Wade Chew, Analytical Chemistry Shared Resources of the Arizona Cancer Center (ACSR), for the mass spectrometry analysis of bile acids in liver and cecal pellets. Funding Information: overexpression of Fxr. The long-term exposure to an n-6HFD increases hepatic Cyp7a1 and BA of Fxr. The long-term exposure to an n-6HFD increases hepatic Cyp7a1 andTG BA accumulation in the accumulation inthe intestine and liver. These effects areattTGenuated in Fxra1 mice. Activation of FXR intestine and liver. These effects are attenuated in Fxra1 mice. Activation of FXR in the intestine in the intestine promotes expressionof FGF15, which activates a signalingcascade in the liver through promotes expression of FGF15, which activates a signaling cascade in the liver through the FGFR4 to the FGFR4 to inhibit Cyp7a1 expression [23,74]. Black arrows denote relationships supported by the inhibitcurrent data. RCyp7a1 expred arrows ession [23depict relation,74]. Black arrships characterizeows denote relationshipsd previously [22,75]. supported by the current data. Red arrows depict relationships characterized previously [22,75]. Author Contributions: S.N.W., M.G.D. and O.I.S. performed the animal and laboratory work and data analysis; T.C.D. supervised the generation of the transgenic mice lines and experimental animal colonies; D.F.R., O.I.S., and T.C.D. contributed to funding acquisition and conceptualization and planning of this study. All authors contributed to the writing and editing of the manuscript. All authors have read and agreed to the published and T.C.D. contributed to funding acquisition and conceptualization and planning of this study. All authors version of the manuscript. contributed to the writing and editing of the manuscript. All authors have read and agreed to the published versioFnuonfdtihneg:m Tahnisu wscorrikp tw. as supported by a grant froUSDA-NIFA, m GRANT12445471; USDA-NIFA Multistate ARZT-1370460-R23-155; The University of Arizona Cancer Center Support Grant P30CA23074; and the Cancer Funding: This work was supported by a grant from USDA-NIFA, GRANT12445471; USDA-NIFA Multistate ARZTBiology Training Grant T32CA009213. -1370460-R23-155; The University of Arizona Cancer Center Support Grant P30CA23074; and the Cancer Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = nov,
day = "1",
doi = "10.3390/ijms21217829",
language = "English (US)",
volume = "21",
pages = "1--21",
journal = "International journal of molecular sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "21",
}