Altered hepatic mitochondrial fatty acid oxidation and ketogenesis in endotoxic rats.
Rat hepatic mitochondrial function, including oxidative phosphorylation, fatty acid oxidative capacity, kinetic parameters of carnitine palmitoyltransferase I (CPT I), and sensitivity of CPT I to malonyl-CoA inhibition were studied in vitro in isolated mitochondria following Escherichia coli lipopolysaccharide (LPS). The hepatic mitochondrial CPT I in LPS-treated rats showed a lower apparent maximum velocity (Vmax) for palmitoyl-CoA and Ki for malonyl-CoA without changes in apparent Km for palmitoyl-CoA. The rate of oxygen consumption or end-product formation of palmitoyl-L-carnitine and octanoate was not altered, but the rate of CPT I-dependent palmitoyl-CoA (plus L-carnitine) oxidation was reduced by LPS, when acetyl-CoA produced via beta-oxidation was directed toward citrate. When acetyl-CoA was directed to acetoacetate, the oxygen consumption rates of palmitoyl-L-carnitine and palmitoyl-CoA (plus L-carnitine) were decreased by LPS, although mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity was not altered. These results indicate that hepatic mitochondria isolated from LPS-treated rats show lower ketogenic and long-chain acyl-CoA oxidative capacity than those of fasted controls, and inhibition of ketogenesis is elicited at a site distal to CPT I in addition to reduction in CPT I activity.
Takeyama
N
N
Department of Emergency and Critical Care Medicine, Kansai Medical University, Osaka, Japan.
Itoh
Y
Y
Kitazawa
Y
Y
Tanaka
T
T
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D004926:Escherichia coli; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D007328:Insulin / Q000097:blood; D007657:Ketone Bodies / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008314:Malonates / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010169:Palmitic Acids / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012772:Shock, Septic / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007657:Ketone Bodies; D008070:Lipopolysaccharides; D008314:Malonates; D010169:Palmitic Acids; D014280:Triglycerides; D005934:Glucagon; D002334:Carnitine O-Palmitoyltransferase