Peroxisome Proliferator-activated Receptor α Induces Hepatic Expression of the Human Bile Acid Glucuronidating UDP-glucuronosyltransferase 2B4 Enzyme

Abstract

Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR␣ agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPAR␣ wild type and null mice revealed that PPAR␣ regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPAR␣ agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR␣, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes.

Dietary Sesame Seed and Its Lignan Increase Both Ascorbic Acid Concentration in Some Tissues and Urinary Excretion by Stimulating Biosynthesis in Rats

“…These results suggest that the increases in the hepatic ascorbic acid concentration and its urinary excretion by dietary sesame seed in Wistar rats are due to the stimulation of ascorbic acid biosynthesis by the induction of a UGT1A/2B-mediated metabolism of sesame lignan or its metabolite. Sugano et al (40)(41)(42) have shown that dietary sesamin stimulates the expression of several genes related to fatty acid metabolism, and have suggested that sesamin is a ligand of peroxisome proliferator-activated receptor ␣, which induces hepatic UGT2B gene expression (43). Therefore, dietary sesamin may stimulate UGT2B gene expression by activating peroxisome proliferator-activated receptor ␣.…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…CYP4 family members were the first fibrate-induced XME target genes shown to be involved in omega-hydroxylation of fatty acids [5]. PPARα is involved in regulation of all phases of the XME system including regulation of many UGTs (UGT1A1, 1A3, 1A4 [51], 1A9 [52], 2B4 [53]). PPARα-induced hepatic UGTs are possibly involved in detoxification of eicosanoids, as discussed in section 4.4.…”

The liver X-receptor alpha controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice

“…17 HepG2 cells were grown as described. 19,20 For RNA analyses, 10 6 HepG2 cells were treated with the indicated concentration of LXR␣ activators for the indicated duration, in the absence or presence of cycloheximide or after a 2-hour pretreatment with actinomycin D. For glucuronidation assays, 20 ϫ 10 6 HepG2 cells were treated with T0901317 (10 mol/L) for 36 hours, and cells were harvested for subsequent purification of microsomes.…”

“…Oligonucleotides and PCR conditions for 18S were as previously described. 19,20 Quantitative PCR analyses of UGT1A3 mRNA levels were determined using primers as indicated in Table 1. Conditions for real-time PCR were 95°C for 10 minutes, 95°C for 15 seconds, and 66°C for 60 seconds for 40 cycles.…”