Development and Characterization of a Mouse Model Overexpressing a Farnesoid-X-Receptor Transgene and Enterohepatic Response to an Omega-6 High Fat Diet

Abstract

A diet high in n-6 polyunsaturated fatty acids (PUFA) 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, which is low in the n-6 PUFA linoleic acid (LA, 2.5%E) (CNTL) with those of a soybean oil-based diet providing 50%E from fat and 28%E from LA (n-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the Fxr1 isoform under the control of the intestine-specific Villin promoter (Fxr1TG) 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 FxrTG littermates; increases the expression of Fxr, ileal bile acid-binding protein (Ibabp), and peroxisome proliferator-activated receptor- (Ppar) in the small intestine, Fxr in the colon, and cholesterol 7-hydroxylase (Cyp7a1) and small heterodimer partner (Shp) in the liver; and augments the levels of total BA in the liver and primary chenodeoxycholic acid (CDCA), cholic acid (CA), and muricholic acid (MCA) in the cecum. Intestinal overexpression of the Fxra1TG augments expression of Ibabp in small intestine and proximal colon. Conversely, it antagonizes n-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of Cyp7a1; and expression of Ppar in the small intestine. We conclude that intestinal Fxr1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of primary bile acids in the cecum.