Abstract
Hepatocyte nuclear factor 4alpha (HNF4alpha) has an important role in regulating the expression of liver-specific genes. Because bile acids are produced from cholesterol in liver and many enzymes involved in their biosynthesis are preferentially expressed in liver, the role of HNF4alpha in the regulation of bile acid production was examined. In mice, unconjugated bile acids are conjugated with taurine by the liver-specific enzymes, bile acid-CoA ligase and bile acid-CoA:amino acid N-acyltransferase (BAT). Mice lacking hepatic HNF4alpha expression exhibited markedly decreased expression of the very long chain acyl-CoA synthase-related gene (VLACSR), a mouse candidate for bile acid-CoA ligase, and BAT. This was associated with markedly elevated levels of unconjugated and glycine-conjugated bile acids in gallbladder. HNF4alpha was found to bind directly to the mouse VLACSR and BAT gene promoters, and the promoter activities were dependent on HNF4alpha-binding sites and HNF4alpha expression. In conclusion, HNF4alpha plays a central role in bile acid conjugation by direct regulation of VLACSR and BAT in vivo.
Highlights
From the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892
Expression of Genes Involved in Bile acids (BAs) Conjugation Is Reduced in Liver-specific HNF4a-null Mice—Free BAs are at first esterified with acetyl-CoA by bile acid-CoA ligase (BAL), and the esterified BAs are conjugated with glycine or taurine by bile acid-CoA:amino acid N-acyltransferase (BAT)
The enzyme activity of BAL has not been analyzed in mouse, but the mouse very long chain acyl-CoA synthase-related gene (VLACSR) gene might be a candidate for a mouse BAL since VLACSR has high homology to both the rat BAL and human VLACSR-H2 that have BAL activities
Summary
Mice lacking hepatic HNF4␣ expression exhibited markedly decreased expression of the very long chain acyl-CoA synthase-related gene (VLACSR), a mouse candidate for bile acid-CoA ligase, and BAT. This was associated with markedly elevated levels of unconjugated and glycine-conjugated bile acids in gallbladder. The biological function of HNF4␣ was investigated in vivo and in vitro using liver-specific HNF4␣null mice These mice exhibit increased unconjugated and glycine-conjugated BAs in gallbladder bile and decreased expression of VLACSR and BAT. These results indicate that HNF4␣ has an important role in the maintenance of BA homeostasis by regulating BA conjugation pathways
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