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

A diet high in -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 -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 -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 ( -6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the isoform under the control of the intestine-specific promoter ( ) were fed the CNTL or -6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the -6HFD supports higher weight gain in both WT and littermates; increases the expression of α , and peroxisome proliferator-activated receptor-γ ( ) in the small intestine, in the colon, and cytochrome P4507A1 ( ) and small heterodimer protein ( ) 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 augments expression of and ileal bile acid-binding protein ( in the small intestine and in the proximal colon. Conversely, it antagonizes -6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of ; and expression of in the small intestine. We conclude that intestinal overexpression represses hepatic de novo BA synthesis and protects against -6HFD-induced accumulation of human-specific primary bile acids in the cecum.