Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

Abstract

We describe a metabolic defect in bile acid synthesis involving a deficiency in 7 ␣ -hydroxylation due to a mutation in the gene for the microsomal oxysterol 7 ␣ -hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3 ␤ -hydroxy-5-cholenoic and 3 ␤ -hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were Ͼ 4,500 times normal. The biochemical findings were consistent with a deficiency in 7 ␣ -hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7 ␣ -hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon.

A functional C–G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians

“…It is located on chromosome 8q21.3 in close linkage to the CYP7A1 gene, suggesting that these genes have evolved via gene duplication. 10 The human CYP7B1 promoter is GCrich and contains three GC-boxes essential for the basal transcription. 11 No common polymorphism has been reported in the human CYP7B1 gene to date.…”

The NAD+ precursors, nicotinic acid and nicotinamide protect cells against apoptosis induced by a multiple stress inducer, deoxycholate

“…Apoptosis-inducing bile salts include deoxycholate (DOC), 2 ± 6 glycodeoxycholate, 7,8 chenodeoxycholate, 2 glycochenodeoxycholate 9,10 and taurochenodeoxycholate. 11 High concentrations of bile salts in the liver are found in association with cholestatic liver disease, in which a deficiency in the secretion of bile salts 12 or an inborn error in bile acid metabolism 13 results in the accumulation of hydrophobic bile acids within hepatocytes. High concentrations of bile salts in the colon usually result from a typical Western-style high fat/low fiber diet, and is associated with increased risk for colon cancer.…”

Bile acids go nuclear!

“…Mutations in bile acid synthetic enzymes can lead to profound liver disease in infancy, those in the ileal bile acid transporter have been linked to a genetic disorder characterized by profound loss of bile acids in the feces, while mutations in the hepatic canalicular bile acid transporter leads to a specific and rare inherited cholestatic disorder of childhood. [5][6][7] All told, the enterohepatic circulation and synthesis of bile acids are intimately linked and tightly regulated, which begs the major question how this could be accomplished. During periods of bile acid loss, bile acid synthesis increases, whereas conversely, in cholestasis, bile acid synthesis markedly diminishes.…”