Hepatocyte Nuclear Factor 4α Is a Central Regulator of Bile Acid Conjugation

Abstract

Hepatocyte nuclear factor 4␣ (HNF4␣) 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 HNF4␣ 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 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. HNF4␣ was found to bind directly to the mouse VLACSR and BAT gene promoters, and the promoter activities were dependent on HNF4␣-binding sites and HNF4␣ expression. In conclusion, HNF4␣ plays a central role in bile acid conjugation by direct regulation of VLACSR and BAT in vivo.

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

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Novel functions of acyl-CoA thioesterases and acyltransferases as auxiliary enzymes in peroxisomal lipid metabolism

“…Baat is regulated by the farnesoid X receptor (FXR) in the rat via an inverted repeat 1 (IR-1) element located in the first intron of the gene and Baat mRNA levels were increased in rats following treatment with a synthetic FXR ligand [161]. Baat expression is also regulated by the hepatocyte nuclear factor 4 alpha (HNF-4α) via a response element in the promoter and expression of the Baat mRNA is not detectable in the HNF-4α knockout mouse, resulting in markedly elevated levels of unconjugated bile acids in gallbladder in this knockout model [162]. Recently Baat expression was shown to be reduced in sepsis in rat via the retinoid X receptor-alpha [163].…”

Role of HNF4α in the superinduction of the IL-1β-activated iNOS gene by oxidative stress

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