Fibrates are a group of hypolipidemic agents that efficiently lower serum triglyceride levels by affecting the expression of many genes involved in lipid metabolism. These effects are exerted via the peroxisome proliferator-activated receptor ␣ (PPAR␣). In addition, fibrates also lower serum cholesterol levels, suggesting a possible link between the PPAR␣ and cholesterol metabolism. Bile acid formation represents an important pathway for elimination of cholesterol, and the sterol 12␣-hydroxylase is a branch-point enzyme in the bile acid biosynthetic pathway, which determines the ratio of cholic acid to chenodeoxycholic acid. Treatment of mice for 1 week with the peroxisome proliferator WY-14,643 or fasting for 24 h both induced the sterol 12␣-hydroxylase mRNA in liver. Using the PPAR␣ knockout mouse model, we show that the induction by both treatments was dependent on the PPAR␣. A reporter plasmid containing a putative peroxisome proliferator-response element (PPRE) identified in the rat sterol 12␣-hydroxylase promoter region was activated by treatment with WY-14,643 in HepG2 cells, being dependent on co-transfection with a PPAR␣ expression plasmid. The rat 12␣-hydroxylase PPRE bound in vitro translated PPAR␣ and retinoid X receptor ␣, albeit weakly, in electrophoretic mobility shift assay. Treatment of wild-type mice with WY-14,643 for 1 week resulted in an increased relative amount of cholic acid, an effect that was abolished in the PPAR␣ null mice, verifying the functionality of the PPRE in vivo.Fibrates and their derivatives constitute a group of hypolipidemic agents that are used in the treatment of hypertriglyceridemia and combined hyperlipidemia. These fibrates belong to a structurally diverse group of compounds known as peroxisome proliferators, which have been shown to cause liver hepatomegaly, proliferation of peroxisomes, and induction of many enzymes involved in peroxisomal and mitochondrial ␤-oxidation and -oxidation of fatty acids (for review, see Ref.

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Ran GTPase has been shown to be involved in host innate immune response, and two alleles, RanT/n and RanC/d, which differ from each other by a single nucleotide, have opposite effects on host innate immune response. In this study, we showed that although intravenous administration in mice with either Ran cDNA using an identical adenovirus (Ad) vector resulted in no significant difference in vector tissue distribution, intraperitoneal administration resulted in effective vector transduction into peritoneal macrophages, coupled with a striking difference in vector tissue distribution in 2 h or less. We further demonstrated the presence of prepackaged RNA in virions of Ad vectors, in cells actively producing Ad virus particles, and in cells very shortly after Ad infection. Real-time PCR analysis confirmed the presence of prepackaged RNA and estimated the copy number to be one per viral genome. The prepackaged viral mRNA could be used for translation into proteins, as shown by experiments in which the transcriptional inhibitor actinomycin-D was used. Hence, translation of Ran proteins from prepackaged viral mRNA immediately after virus uncoating in the cytoplasm is one mechanism that would account for an early difference in Ad-vector tissue distribution after efficient gene transfer into macrophages.

Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7 ␣ -hydroxylase gene ( CYP7A1 ) in the bile acid biosynthetic pathway in the liver. Farnesoid X receptor (FXR) repressed CYP7A1 /Luc reporter activity in a transfection assay in human liver-derived HepG2 cells, but not in human embryonic kidney (HEK) 293 cells. FXR-binding activity was required for bile acid repression of CYP7A1 transcription despite the fact that FXR did not bind to the CYP7A1 promoter. FXR-induced liverspecific factors must be required for mediating bile acid repression. Bile acids and FXR repressed endogenous CYP7A1 but stimulated ␣ -fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression in HepG2 cells. Feeding of rats with chenodeoxycholic acid repressed CYP7A1, induced FTF, but had no effect on SHP mRNA expression in the liver. FTF strongly repressed CYP7A1 transcription in a dose-dependent manner, and SHP further inhibited CYP7A1 in HepG2 cells, but not in HEK 293 cells. FXR only moderately stimulated SHP transcription, whereas FTF strongly inhibited SHP transcription in HepG2 cells. Results revealed that FTF was a dominant negative factor that was induced by bile acid-activated FXR to inhibit both CYP7A1 and SHP transcription. Differential regulation of FTF and SHP expression by bile acids may explain the wide variation in CYP7A1 expression and the rate of bile acid synthesis and regulation in different species. -Chen, W., E. Owsley, Y. Yang, D. Stroup, and J. Y. L. Chiang. Nuclear receptor-mediated repression of human cholesterol 7 ␣ -hydroxylase gene transcription by bile acids.