Impaired ketogenesis is a major mechanism for disturbed hepatic fatty acid metabolism in rats with long-term cholestasis and after relief of biliary obstruction

Background/Aims: Rats with long-term cholestasis have reduced ketosis of unknown origin. Methods: Fatty acid metabolism was studied in starved rats with biliary obstruction for 4 weeks (bile duct ligated RATS= BDL rats), and 3, 7, 14, 28 and 84 days after reversal of biliary obstruction by Roux-en-Y anastomosis (RY rats), and in sham-operated control rats. Results: BDL rats had reduced β-hydroxybutyrate concentrations in plasma (0.25±0.10 vs. 0.75±0.20 mmol/l) and liver (2.57±0.20 vs. 4.63±0.61 μmol/g) which increased after restoring bile flow. Hepatic expression and activity of carnitine palmitoyltransferase I (CPT I) or CPT II were unaffected or decreased in BDL rats, respectively, and increased after restoring bile flow. Oxidative metabolism of different substrates by isolated liver mitochondria and activation of palmitate were reduced in BDL rats and recovered 7–14 days after restoring bile flow. Ketogenesis was decreased in mitochondria from BDL rats and recovered 3 months after restoring bile flow. Both mRNA and protein expression of hydroxymethylglutaryl-coenzyme A synthase (HMG-CoA synthase), the rate-limiting enzyme of ketogenesis, was reduced in livers of BDL rats and increased after reversing biliary obstruction. Conclusions: In BDL rats, impairment of hepatic fatty acid metabolism is multifactorial. After reversing biliary obstruction, reduced activity of HMG-CoA synthase is the major factor.