A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet.

Spencer N Wren,Donato F Romagnolo,Micah G Donovan,Ornella I Selmin,Tom C Doetschman

doi:10.3390/ijms21217829

Spencer N Wren, Donato F Romagnolo + Show 3 more

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https://doi.org/10.3390/ijms21217829

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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.

Highlights

The consumption of n-6 compared to other (e.g., n-3) polyunsaturated fatty acids (PUFAs) has increased considerably in the United States during recent decades
We report that the overexpression of an intestinal Fxrα1TG antagonizes the n-6HFD-dependent accumulation of primary bile acid (BA) in the cecum and liver through activation in the intestine of factors involved in their reabsorption, and repression in the liver of enzymes involved in de novo BA synthesis
The present study addresses the effects of an n-6HFD enriched in linoleic acid (LA) on intestinal and hepatic expression of genes involved in BA metabolism, and the modifying role of intestinal FXRα1TG expression on enterohepatic BA homeostasis

Summary

Introduction

The consumption of n-6 compared to other (e.g., n-3) polyunsaturated fatty acids (PUFAs) has increased considerably in the United States during recent decades. The rise in PUFA consumption is consistent with recommendations to reduce intake of saturated fatty acids (SFAs) [2,3]. This is in spite of evidence about the potential intestinal proinflammatory [4,5] and carcinogenic [6] properties of diets rich in n-6 PUFAs. Consuming a diet high in n-6 PUFAs increases the risk of obesity [7], which further increases the risk of colon cancer [8] and liver steatosis [9]. Pathologies of the liver and colon are both associated with dysregulation of bile acid (BA) metabolism [10,11,12]

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