alpha(1)-fetoprotein transcription factor (FTF)/liver receptor homolog-1 (LRH-1) is an essential lipogenic regulator

Abstract

alpha(1)-Fetoprotein transcription factor (FTF), also known as liver receptor homolog 1 (LRH-1) is highly expressed in the liver and intestine, where it is implicated in the regulation of cholesterol, bile acid and steroid hormone homeostasis. FTF is an important regulator of bile acid metabolism. We show here that FTF plays a key regulatory role in lipid homeostasis including triglyceride and cholesterol homeostasis. FTF deficient mice developed lower levels of serum triglyceride and cholesterol as a result of lower expression of several hepatic FTF target genes. Chenodeoxycholic acid repressed FTF expression resulting in a decrease in serum triglyceride in wild-type mice. The absence of chenodeoxycholic acid-mediated repression in FTF(+/-) mice demonstrated the essential role of FTF in triglyceride metabolism. Taken together, our results identify the nuclear receptor FTF as a central regulator of lipid metabolism.

Keywords: bile acids; cholesterol; knockout mice; nuclear receptor; triglycerides.

Fig. 1

Differential FTF protein and mRNA levels in wild-type and FTF^+/- mice fed ad libitum (129 SV background). FTF mRNA and protein were quantified by RT-PCR and western blotting respectively, as indicated in Materials and methods. An autoradiograph for the western blot is shown at the bottom, with HDAC as a loading control. Values represent the means ± S.D. from three mice/group. * p < 0.05 compare to wild-type mice.

Fig. 2

FTF overexpression increased serum triglyceride and mature nuclear SREBP-1c in C57BL/6 mice. Male mice (three to five/group, 40 days old, fed ad libitum) were injected with the indicated viruses. Four days later, blood was collected and triglycerides and cholesterol quantified (top panel). Values represent the means ± S.D. * p < 0.05 compared to control virus. Bottom panel shows a Western blot performed on nuclear extracts to quantify FTF and SREBP-1. Histone deacetylase (HDAC) was used as a control.

Fig. 3

Chenodeoxycholic feeding decreased serum triglyceride wild-type mice but not in FTF^+/- mice. Wild-type and FTF^+/- mice (50 days old, 129SV background, three per group) were fed ad libitum either a control diet or the same diet supplemented with 0.25 % chenodeoxycholic acid for 2 days. Serum and liver were collected and used to quantify triglycerides and total cholesterol (top panel), FTF and SHP mRNA (bottom panel), and FTF and HDAC nuclear proteins (bottom panel, insert) as indicated in Materials and methods. * p < 0.05, ** p = 0.07 compare to wild-type mice fed the control diet.

Fig. 4

FTF^+/- mice have lower liver triglyceride content than wild-type mice. Triglycerides, fatty acids and cholesterol were quantified in the liver of wild-type and FTF^+/- male mice (50 days old, 129SV background, three to five/group) as indicated in Materials and methods. * p < 0.05 compare to wild-type mice; **p = 0.07.