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,Stephan Krähenbühl

doi:10.1194/jlr.m200200-jlr200

Markus Spaniol, Priska Kaufmann + Show 6 more

Open Access

https://doi.org/10.1194/jlr.m200200-jlr200

Copy DOI

Abstract

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.

Highlights

Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis
The studies were carried out to elucidate the principle mechanisms leading to liver steatosis in rats with systemic carnitine deficiency due to treatment with THP
Our study demonstrates that THP-treated rats have an ‫ف‬70% reduction in the hepatic carnitine content, reduced in vivo metabolism of palmitate, liver steatosis, accumulation of long-chain acyl-CoAs in the cytosol of the hepatocytes, hepatic proliferation of peroxisomes, and increased plasma VLDL

Summary

Introduction

Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis. 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. Since carnitine is essential for transport of long-chain fatty acids into the mitochondrial matrix [14], it can be speculated that at least the microvesicular part of liver steatosis in THP-treated rats could be caused by hepatic carnitine deficiency. In support of this assumption, both in children with primary systemic carnitine deficiency and in mice with systemic carnitine deficiency (JVS mice), microvesic-.

Objectives

Methods

Results

Conclusion