Abstract
Class I alcohol dehydrogenases (ADH1s) are the rate-limiting enzymes for ethanol and vitamin A (retinol) metabolism in the liver. Because previous studies have shown that human ADH1 enzymes may participate in bile acid metabolism, we investigated whether the bile acid-activated nuclear receptor farnesoid X receptor (FXR) regulates ADH1 genes. In human hepatocytes, both the endogenous FXR ligand chenodeoxycholic acid and synthetic FXR-specific agonist GW4064 increased ADH1 mRNA, protein, and activity. Moreover, overexpression of a constitutively active form of FXR induced ADH1A and ADH1B expression, whereas silencing of FXR abolished the effects of FXR agonists on ADH1 expression and activity. Transient transfection studies and electrophoretic mobility shift assays revealed functional FXR response elements in the ADH1A and ADH1B proximal promoters, thus indicating that both genes are direct targets of FXR. These findings provide the first evidence for direct connection of bile acid signaling and alcohol metabolism.
Highlights
Class I alcohol dehydrogenases (ADH1s) are the rate-limiting enzymes for ethanol and vitamin A metabolism in the liver
The present study identifies the human ADH1A and ADH1B genes as direct targets of the bile acid-activated nuclear receptor farnesoid X receptor (FXR)
Following: a) the expression of ADH1A and ADH1B is induced in HepG2 cells, Huh7 cells, and primary human hepatocytes in response to natural and synthetic FXR ligands; b) overexpression of constitutively active FXR augments ADH1A and ADH1B mRNA levels; c) IR1 elements identified at the proximal promoters of ADH1A and ADH1B are able to confer FXR response and bind FXRRXR heterodimers; d) alcohol dehydrogenase activity is increased upon FXR activation; and e) silencing of FXR abolished the effects of FXR agonists on class I alcohol dehydrogenase (ADH1) expression and activity
Summary
Class I alcohol dehydrogenases (ADH1s) are the rate-limiting enzymes for ethanol and vitamin A (retinol) metabolism in the liver. Because previous studies have shown that human ADH1 enzymes may participate in bile acid metabolism, we investigated whether the bile acid-activated nuclear receptor farnesoid X receptor (FXR) regulates ADH1 genes In human hepatocytes, both the endogenous FXR ligand chenodeoxycholic acid and synthetic FXR-specific agonist GW4064 increased ADH1 mRNA, protein, and activity. Transient transfection studies and electrophoretic mobility shift assays revealed functional FXR response elements in the ADH1A and ADH1B proximal promoters, indicating that both genes are direct targets of FXR. These findings provide the first evidence for direct connection of bile acid signaling and alcohol metabolism.— Langhi, C., E.
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