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

Rats with longterm cholestasis have reduced ketosis during starvation. Beca use it is unclear whether this is also the case in short-term cholestasis, we investigated hepatic fatty acid metabolism in rats with bile duct Ligati on for 5 days (BDE5, n = II) or 10 days (BDL10, n = 11) and compared the fi ndings with those made with pair-fed control rats (CON5 and CON10, n = II). The plasma beta -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 diff erent between BDL and control rats. Production of ketone bodies from [C-14] palmitate was reduced by 40% in mitochondria from EDL rats at both time poi nts, whereas production of (CO2)-C-14 was maintained. These findings indica ted intact function of the respiratory chain, Krebs cycle, and B-oxidation and suggested impaired ketogenesis (HMG-CoA pathway). Accordingly, the form ation 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 redu ced hepatic mRNA and protein levels. We conclude that short-term cholestasi s in rats leads to impaired hepatic fatty acid metabolism due to impaired k etogenesis. Ketogenesis is impaired because of decreased mRNA levels of HMG -CoA synthase, leading to reduced hepatic protein levels and to decreased a ctivity of this key enzyme of ketogenesis.