Decreased carnitine biosynthesis in rats with secondary biliary cirrhosis

Authors

  • Dr. Stephan Krähenbühl,

    1. Departments of Medicine and Pharmacology, Case Western Reserve University, VA Medical Center, Cleveland, OH
    Current affiliation:
    1. Division of Clinical Pharmacology, University Hospital, Basel, Switzerland
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  • Dr. Eric P. Brass,

    1. Departments of Medicine and Pharmacology, Case Western Reserve University, VA Medical Center, Cleveland, OH
    Current affiliation:
    1. Department of Medicine, Harbor-UCLA Medical Ctr., Torrance, CA
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  • Charles L. Hoppel M.D.

    Corresponding author
    1. Departments of Medicine and Pharmacology, Case Western Reserve University, VA Medical Center, Cleveland, OH
    • Medical Research Service (151W), VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106.fax:(216) 229-8509
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Abstract

Carnitine biosynthesis was investigated in rats with secondary biliary cirrhosis induced by bile duct ligation (BDL) for 4 weeks (n = 5) and in pair-fed, sham-operated control rats (n = 4). Control rats were pair-fed to BDL rats, and all rats were fed an artificial diet with negligible contents of carnitine, butyrobetaine, or trimethyllysine. Biosynthesis of carnitine and its precursors was determined by measuring their excretion in urine and accumulation in the body of the animals. Four weeks after BDL, total carnitine content was increased by 33% in livers from BDL rats when compared with control rats, but was unchanged in skeletal muscle and whole carcass. The plasma total carnitine concentration averaged 29.0 ± 4.1 vs. 46.4 ± 7.3 μmol/L in BDL rats and control rats, respectively. Urinary total carnitine excretion was reduced by 56% in BDL rats as compared with control rats. Carnitine biosynthesis was significantly decreased in BDL rats (0.45 ± 0.19 vs. 0.93 ± 0.08 μmol/100 g body weight/d in BDL and control rats, respectively). The tissue content of free and protein-linked trimethyllysine, a carnitine precursor, and trimethyllysine plasma concentrations were not different between BDL and control rats. However, urinary trimethyllysine excretion was increased 5-fold in BDL rats and approximated glomerular filtration. In contrast, urinary excretion of butyrobetaine, the direct carnitine precursor, was decreased by 40% in BDL rats as compared with control rats. Trimethyllysine biosynthesis was not different, but butyrobetaine biosynthesis was decreased by 51% in BDL as compared with control rats. In conclusion, carnitine biosynthesis is decreased in BDL rats as a result of a defect in the conversion of trimethyllysine to butyrobetaine.

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