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Papers In Press, published online ahead of print October 16, 2002
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Submitted on May 20, 2002
University Hospital, Basel CH-4031
Corresponding Author: kraehenbuehl{at}uhbs.ch
Summary Background: Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis. Aims: To investigate the mechanisms leading to steatosis in THP-induced carnitine deficiency. Methods: Rats were treated with THP (20 mg/100 g) for 3 or 6 weeks, and were studied after starvation for 24 hours. Results: 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 â -oxidation at 3 weeks, but reduced activities at 6 weeks of THP treatment. Ketogenesis was not affected. The hepatic content of coenzyme A was increased by 23% at 3 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. Conclusions: 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 and phospholipid concentrations and peroxisomal proliferation. Key words: systemic carnitine deficiency, liver steatosis, mitochondrial and peroxisomal beta-oxidation, peroxisomal proliferation, trimethylhydraziniumpropionate
Revised on October 4, 2002
Accepted on October 10, 2002
Mechanisms of liver steatosis in rats with systemic carnitinedeficiency due to treatment with trimethylhydraziniumpropionate
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