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Journal of Lipid Research, Vol. 42, 22-30, January 2001
Copyright © 2001 by Lipid Research, Inc.

Original Article

Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism

Correspondence to: Stephan Krähenbühl, To whom correspondence should be addressed: Stephan Krähenbühl, Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, CH-4031 Basel, Switzerland.

Rats with long-term cholestasis have reduced ketosis during starvation. Because it is unclear whether this is also the case in short-term cholestasis, we investigated hepatic fatty acid metabolism in rats with bile duct ligation for 5 days (BDL5, n = 11) or 10 days (BDL10, n = 11) and compared the findings with those made with pair-fed control rats (CON5 and CON10, n = 11). The plasma ß-hydroxybutyrate concentration was reduced in BDL rats (0.54 ± 0.10 vs. 0.83 ± 0.30 mM at 5 days and 0.59 ± 0.24 vs. 0.88 ± 0.09 mM at 10 days in BDL and control rats, respectively). In isolated liver mitochondria, state 3 oxidation rates for various substrates were not different between BDL and control rats. Production of ketone bodies from [¹⁴C]palmitate was reduced by 40% in mitochondria from BDL rats at both time points, whereas production of ¹⁴CO₂ was maintained. These findings indicated intact function of the respiratory chain, Krebs cycle, and ß-oxidation and suggested impaired ketogenesis (HMG-CoA pathway). Accordingly, the formation of acetoacetate from acetyl-CoA by disrupted mitochondria was reduced in BDL rats at 5 days (2.1 ± 1.0 vs. 4.8 ± 1.9 nmol/min per mg protein) and at 10 days (1.7 ± 1.0 vs. 6.2 ± 1.9 nmol/min per mg protein). The principal defect could be localized at the rate-limiting enzyme of the HMG-CoA pathway, HMG-CoA synthase, which revealed decreased activity, and reduced hepatic mRNA and protein levels.

We conclude that short-term cholestasis in rats leads to impaired hepatic fatty acid metabolism due to impaired ketogenesis. Ketogenesis is impaired because of decreased mRNA levels of HMG-CoA synthase, leading to reduced hepatic protein levels and to decreased activity of this key enzyme of ketogenesis. — Lang, C., M. Schäfer, D. Serra, F. G. Hegardt, L. Krähenbühl, and S. Krähenbühl. Impaired hepatic fatty acid oxidation in rats with short-term cholestasis: characterization and mechanism. J. Lipid Res. 2001. 42: 22;–30.

Supplementary key words: mitochondria, respiratory chain, ß-oxidation, HMG-CoA pathway, ketogenesis

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