Importance of Peroxisomes in the Formation of Chenodeoxycholic Acid in Human Liver. Metabolism of 3α,7α-Dihydroxy-5β-cholestanoic Acid in Zellweger Syndrome

Abstract

ABSTRACT. Infantile Zellweger syndrome belongs to the group of peroxisomal disorders that lack peroxisomes. Both trihydroxycoprostanic acid (THCA), the precursor to cholic acid, and dihydroxycoprostanic acid (DHCA), the precursor to chenodeoxycholic acid, accumulate in this disease. In previous studies, we have shown that liver peroxisomes are required for the conversion of THCA into cholic acid both in vitro and in vivo by measuring a defective conversion in infants with Zellweger syndrome. In our present study, the conversion of DHCA into chenodeoxycholic acid has been measured in an infant with Zellweger syndrome to evaluate the importance of liver peroxisomes for the formation of chenodeoxycholic acid. Coprostanic acidemia was present from the second day of life with high levels of THCA and only trace amounts of DHCA. The conversion of i.v. administered 13H]DHCA into chenodeoxycholic acid was only 7% compared with the 80% conversion in an analogous study in an adult. There was, however, a rapid incorporation of 'H into biliary THCA and, after a lag phase, the 3H was incorporated into biliary cholic acid. After 72 h, 15% of 13H]DHCA was converted to cholic acid. The pool size of DHCA was 1.2 mg/m2 and the pool size of both cholic acid and chenodeoxycholic acid was markedly reduced. The renal excretion of cholic acid was more efficient than that of the less polar chenodeoxycholic acid. More polar metabolites of DHCA and THCA are formed in alternative metabolic pathways facilitating renal excretion of these toxic intermediates. We conclude that liver peroxisomes are essential for a normal conversion of DHCA into chenodeoxycholic acid. (Pediarr Res 29: 64-69, 1991) Abbreviations DHCA, 3a,7a-dihydroxycoprostanic acid (or 3a,7a-dihydroxy-50-cholestanoic acid) THCA, 3a,7a,l2a-trihydroxycoprostanic acid C2,-dicarboxylic acid, 3a,7a,12a-trihydroxy-27-carboxymethylcoprostanic acid GC-MS, gas chromatography-mass spectrometry

The Human Bile Acid-CoA:Amino Acid N-Acyltransferase Functions in the Conjugation of Fatty Acids to Glycine

“…Our data consolidate this point, as THCA-CoA proved to be a very poor substrate in comparison with CA-CoA and CDCA-CoA. The low activity with THCA-CoA is consistent with the observed accumulation of THCA in the serum of Zellweger patients, in which bile acid synthesis is severely impaired (30).…”

Peroxisome Proliferator-induced Long Chain Acyl-CoA Thioesterases Comprise a Highly Conserved Novel Multi-gene Family Involved in Lipid Metabolism

“…The BAT enzyme is also expressed mainly in liver and kidney, suggesting that bile acid formation occurs in these two tissues (35). Bile acids are formed by ␤-oxidation of cholesterol, followed by conjugation to amino acids in peroxisomes (36). It has previously been demonstrated that clofibrate treatment of rats results in decreased fecal bile acid output (37), suggesting decreased bile acid formation.…”