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

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 Fxr1 isoform under the control of the intestine-specific Villin promoter (Fxr1TG) 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 FxrTG 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 Fxr1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of primary bile acids in the cecum