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Journal of Lipid Research, Vol. 44, 144-153, January 2003
Copyright © 2003 by Lipid Research, Inc.

Mechanisms of liver steatosis in rats with systemic carnitine deficiency due to treatment with trimethylhydraziniumpropionate

Markus Spaniol^*, Priska Kaufmann^*, Konstantin Beier, Jenny Wüthrich^*, Michael Török^*, Hubert Scharnagl, Winfried März and Stephan Krähenbühl^1,*

^* Division of Clinical Pharmacology and Toxicology, University Hospital, Basel, Switzerland
Institute of Anatomy, University of Basel, Switzerland
Division of Clinical Chemistry, Department of Medicine, Albert Ludwigs-University, Freiburg, Germany

¹ To whom correspondence should be addressed. e-mail: kraehenbuehl{at}uhbs.ch

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 ß-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.

Abbreviations: AOX, acyl-CoA oxidase; Complex I, NADH:decylubiquinone-1 oxidoreductase; Complex II, succinate:dichlorindophenol oxidoreductase; Complex III, Ubiquinol:ferricytochrome c oxidoreductase; Complex IV, Cytochrome c oxidase; CPT, carnitine palmitoyltransferase; DAB, diaminobenzidine; FC, free cholesterol; jvs, juvenile visceral steatosis; PIPES, piperazine-N,N'-bis[2-ethanesulfonic] acid; PPAR, peroxisome proliferator-activated receptor; TC, total cholesterol; THP, 3-(2,2,2-trimethylhydrazinium)propionate

Supplementary key words mitochondrial ß-oxidation • peroxisomal ß-oxidation • peroxisomal proliferation

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