Abstract
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.
Highlights
Rats with long-term cholestasis have reduced ketosis during starvation
While the plasma free fatty acid concentration was not different between BDL and control rats, the plasma -hydroxybutyrate concentration was decreased in BDL rats at both 5 and 10 days after surgery, compatible with impaired hepatic fatty acid metabolism
Control rats (CON5 and CON10, n ϭ 11 for both groups) were sham operated and pair fed with BDL rats throughout the study
Summary
Rats with long-term cholestasis have reduced ketosis during starvation. Because it is unclear whether this is 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). 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 -oxidation and suggested impaired ketogenesis (HMG-CoA pathway). Studies had shown that the production of ketone bodies by perfused livers from rats with long-term bile duct ligation is reduced [7]. Long-term bile duct ligation is associated with reduced activities of complexes I and III of the respiratory chain of liver mitochondria [2, 8], a finding considered to be responsible for the observed impairment of hepatic fatty acid oxidation in this animal model of biliary cirrhosis.
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