MECHANISMS OF IMPAIRED HEPATIC FATTY-ACID METABOLISM IN RATS WITH LONG-TERM BILE-DUCT LIGATION

Hepatic metabolism of fatty acids is impaired in experimental animals with long-term bile duct ligation. To characterize the underlying defe cts, fatty acid metabolism was investigated in isolated hepatocytes an d isolated liver mitochondria from rats subjected to long-term bile du ct ligation or sham surgery. After starvation for 24 hr, the plasma be ta-hydroxybutyrate concentration was decreased in rats with bile duct ligation as compared with control rats. Production of beta-hydroxybuty rate from butyrate, octanoate and palmitate by hepatocytes isolated fr om rats subjected to bile duct ligation was also decreased. Liver mito chondria from rats subjected to bile duct ligation showed decreased st ate 3 oxidation rates for L-glutamate, succinate, duroquinone, and fat ty acids but not for ascorbate as substrate. State 3u oxidation rates (uncoupling with dinitrophenol) and activities of mitochondrial oxidas es were also decreased in mitochondria from rats subjected to bile duc t Ligation. Direct assessment of the activities of the subunits of the electron transport chain revealed reduced activities of complex I, co mplex II and complex III in mitochondria from rats subjected to bile d uct ligation. Activities of the beta-oxidation enzymes specific for sh ort-chain fatty acids were all reduced in rats subjected to bile duct ligation. Mitochondrial protein content per hepatocyte was increased b y 32% in rats subjected to bile duct ligation compared with control ra ts. Thus the studies directly demonstrate mitochondrial defects in fat ty acid oxidation in rats subjected to bile duct ligation, which expla in decreased ketosis during starvation.