| Summary: | 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 β-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 β-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.
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