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J. Biol. Chem., Vol. 282, Issue 29, 20816-20826, July 20, 2007

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Regulation of Lipid Flux between Liver and Adipose Tissue during Transient Hepatic Steatosis in Carnitine-depleted Rats^*

Pascal Degrace, Laurent Demizieux, Zhen-yu Du, Joseph Gresti, Laurent Caverot, Louiza Djaouti, Tony Jourdan, Bastien Moindrot, Jean-Claude Guilland, Jean-Franois Hocquette^¶, and Pierre Clouet¹

From the UMR 866 INSERM-UB, Equipe Physiopathologie des dyslipidémies, Faculté des Sciences, 21000 Dijon, the LPPCE, FacultédeMédecine, Université de Bourgogne, 21000 Dijon, and the ^¶Unité de Recherches sur les Herbivores, INRA, 63122 Saint-Genès-Champanelle, France

Rats with carnitine deficiency due to trimethylhydrazinium propionate (mildronate) administered at 80 mg/100 g body weight per day for 10 days developed liver steatosis only upon fasting. This study aimed to determine whether the transient steatosis resulted from triglyceride accumulation due to the amount of fatty acids preserved through impaired fatty acid oxidation and/or from up-regulation of lipid exchange between liver and adipose tissue. In liver, mildronate decreased the carnitine content by 13-fold and, in fasted rats, lowered the palmitate oxidation rate by 50% in the perfused organ, increased 9-fold the triglyceride content, and doubled the hepatic very low density lipoprotein secretion rate. Concomitantly, triglyceridemia was 13-fold greater than in controls. Hepatic carnitine palmitoyltransferase I activity and palmitate oxidation capacities measured in vitro were increased after treatment. Gene expression of hepatic proteins involved in fatty acid oxidation, triglyceride formation, and lipid uptake were all increased and were associated with increased hepatic free fatty acid content in treated rats. In periepididymal adipose tissue, mildronate markedly increased lipoprotein lipase and hormone-sensitive lipase activities in fed and fasted rats, respectively. On refeeding, carnitine-depleted rats exhibited a rapid decrease in blood triglycerides and free fatty acids, then after 2 h, a marked drop of liver triglycerides and a progressive decrease in liver free fatty acids. Data show that up-regulation of liver activities, peripheral lipolysis, and lipoprotein lipase activity were likely essential factors for excess fat deposit and release alternately occurring in liver and adipose tissue of carnitine-depleted rats during the fed/fasted transition.

Received for publication, December 12, 2006 , and in revised form, May 11, 2007.

^* This work was supported by grants from the Ministère de la Recherche et de la Technologie (Paris, France) and the Région Bourgogne (Dijon, France). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Faculté des Sciences Gabriel, 6 Boulevard Gabriel, Université de Bourgogne, 21000 Dijon, France. Tel.: 33-380-39-63-23; Fax: 33-380-39-63-30; E-mail: pclouet{at}u-bourgogne.fr.

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