Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhydraziniumpropionate.
Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis. This study aims to investigate the mechanisms leading to steatosis in THP-induced carnitine deficiency. Rats were treated with THP (20 mg/100 g) for 3 or 6 weeks and were studied after starvation for 24 h. Rats treated with THP had reduced in vivo palmitate metabolism and developed mixed liver steatosis at both time points. The hepatic carnitine pool was reduced in THP-treated rats by 65% to 75% at both time points. Liver mitochondria from THP-treated rats had increased oxidative metabolism of various substrates and of beta-oxidation at 3 weeks, but reduced activities at 6 weeks of THP treatment. Ketogenesis was not affected. The hepatic content of CoA was increased by 23% at 3 weeks and by 40% at 6 weeks in THP treated rats. The cytosolic content of long-chain acyl-CoAs was increased and the mitochondrial content decreased in hepatocytes of THP treated rats, compatible with decreased activity of carnitine palmitoyltransferase I in vivo. THP-treated rats showed hepatic peroxisomal proliferation and increased plasma VLDL triglyceride and phospholipid concentrations at both time points. A reduction in the hepatic carnitine pool is the principle mechanism leading to impaired hepatic fatty acid metabolism and liver steatosis in THP-treated rats. Cytosolic accumulation of long-chain acyl-CoAs is associated with increased plasma VLDL triglyceride, phospholipid concentrations, and peroxisomal proliferation.
Spaniol
Markus
M
Division of Clinical Pharmacology and Toxicology, University Hospital, Basel, Switzerland.
Kaufmann
Priska
P
Beier
Konstantin
K
Wüthrich
Jenny
J
Török
Michael
M
Scharnagl
Hubert
H
März
Winfried
W
Krähenbühl
Stephan
S
D042962:Acyl-CoA Oxidase; D000818:Animals; D002331:Carnitine / Q000032:analysis / Q000097:blood / Q000172:deficiency*; D056486:Chemical and Drug Induced Liver Injury; D004579:Electron Transport; D007657:Ketone Bodies / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology; D008763:Methylhydrazines / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D007657:Ketone Bodies; D008055:Lipids; D008074:Lipoproteins; D008763:Methylhydrazines; D010168:Palmitates; C050147:3-(2,2,2-trimethylhydrazine)propionate; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D002331:Carnitine