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

Spaniol, Markus; Kaufmann, Priska; Beier, Konstantin; Wüthrich, Jenny; Török, Michael; Scharnagl, Hubert; März, Winfried; Krähenbühl, Stephan

doi:10.1194/jlr.m200200-jlr200

Cited by 46 publications

(41 citation statements)

References 58 publications

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“…KB that are nearly exclusively synthesized within liver cells from ␤-oxidation products were recovered in comparable concentrations in blood of both control and treated rats (Table 1). This surprising observation is consistent with results of another study using the same drug over longer times (46). Indeed, it has been shown that acetylCoA released in low amounts from poorly active ␤-oxidation reactions more easily enters the KB synthesis pathway than the tricarboxylic acid cycle that is inversely more used under conditions of stimulated ␤-oxidation (51).…”

Section: Discussionsupporting

confidence: 89%

“…Our data show that the marked fat deposition observed in the liver of mildronate-treated rats after a 18-h fast nearly disappeared after ϳ4 h of refeeding. These results strongly contrasted with the much lower TG accumulation obtained using 4-fold less mildronate over at least a double time period (46). The puzzling transient steatosis apparent only during fasting indicated that the liver esterification capacities were increased and strongly suggested that a large amount of fat accumulating within liver cells originated from other tissues.…”

Section: Discussionmentioning

confidence: 72%

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

Degrace

Demizieux

et al. 2007

Journal of Biological Chemistry

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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 upregulation of lipid exchange between liver and adipose tissue. In liver, mildronate decreased the carnitine content by ϳ13-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 ϳ2 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.Fat is mainly deposited in adipose tissue, but is also observed in liver biopsies of humans suffering from disorders originating, for instance, from alcohol abuse, diabetes (1), or intoxications (2). Fat storage usually results from the imbalance of the partitioning of lipids between their utilization as energy sources and their preservation or synthesis as triglycerides (TG) 2 initially provided by excess feeding or increased lipogenesis (3). Liver steatosis may also exist when the lipoprotein secretion mechanisms are impaired (4, 5). Genetic models of animal obesity (6, 7) and overweight humans (8, 9) have provided information on regulations occurring in adipose tissue and liver, in which fat deposit may be the consequence of actions mediated by insulin, such as inhibition of fatty acid (FA) oxidation (10) or increased lipogenesis (11,12), and even of hypothalamic injuries (13). Experimental studies have been undertaken to amplify the inhibition of the FA oxidation pathway with drugs that reduce the carnitine-dependent transfer of FA into mitochondria, for example, etomoxir for the carnitine palmitoyltransferase (CPT) I step (14), L-aminocarnitine for the CPT II step (15), or 3,2,2,2-trimethylhydrazinium propionate (mildronate) for liver carnitine biosynth...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 72%

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

Degrace

Demizieux

et al. 2007

Journal of Biological Chemistry

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“…From frozen tissues, total RNA was obtained using QIAGEN mini-prep columns (Qiagen, Hombrechtikon, Switzerland) as described previously (Spaniol et al, 2003).…”

Section: Carnitine and Acylcarnitines In Plasma Urine And Tissuesmentioning

confidence: 99%

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Schürch

Todesco

Nováková

et al. 2010

European Journal of Pharmacology

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Previous findings in rats and in human vegetarians suggest that the plasma carnitine concentration and/or carnitine ingestion may influence the renal reabsorption of carnitine. We tested this hypothesis in rats with secondary carnitine deficiency following treatment with N-trimethyl-hydrazine-3-propionate (THP) for 2 weeks and rats treated with excess L-carnitine for 2 weeks. Compared to untreated control rats, treatment with THP was associated with an approximately 70% decrease in plasma carnitine and with a 74% decrease in the skeletal muscle carnitine content. In contrast, treatment with Lcarnitine increased plasma carnitine levels by 80% and the skeletal muscle carnitine content by 50%. Treatment with L-carnitine affected neither the activity of carnitine transport into isolated renal brush border membrane vesicles, nor renal mRNA expression of the carnitine transporter OCTN2. In contrast, in carnitine deficient rats, carnitine transport into isolated brush border membrane vesicles was increased 1.9-fold compared to untreated control rats. Similarly, renal mRNA expression of OCTN2 increased by a factor of 1.7 in carnitine deficient rats, whereas OCTN2 mRNA expression remained unchanged in gut, liver or skeletal muscle. Our study supports the hypothesis that a decrease in the carnitine plasma and/or glomerular filtrate concentration increases renal expression and activity of OCTN2.

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“…Two to three weeks of THP treatment has been shown to reduce the carnitine content of heart, liver, plasma, and skeletal muscle (quadriceps femoris) by 72-83% (37) to cause liver steatosis and peroxisomal proliferation (38) and impaired myocardial function (47). To date, the characterization of this model of carnitine deficiency has focused predominantly upon THP's effect upon liver, heart, and kidney, whereas skeletal muscle metabolism and function have received little attention.…”

mentioning

confidence: 99%

Contractile function and energy metabolism of skeletal muscle in rats with secondary carnitine deficiency

Roberts

Bouitbir

Bonifacio

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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-The consequences of carnitine depletion upon metabolic and contractile characteristics of skeletal muscle remain largely unexplored. Therefore, we investigated the effect of N-trimethyl-hydrazine-3-propionate (THP) administration, a carnitine analog inhibiting carnitine biosynthesis and renal reabsorption of carnitine, on skeletal muscle function and energy metabolism. Male Sprague-Dawley rats were fed a standard rat chow in the absence (CON; n ϭ 8) or presence of THP (n ϭ 8) for 3 wk. Following treatment, rats were fasted for 24 h prior to excision of their soleus and EDL muscles for biochemical characterization at rest and following 5 min of contraction in vitro. THP treatment reduced the carnitine pool by ϳ80% in both soleus and EDL muscles compared with CON. Carnitine depletion was associated with a 30% decrease soleus muscle weight, whereas contractile function (expressed per gram of muscle), free coenzyme A, and water content remained unaltered from CON. Muscle fiber distribution and fiber area remained unaffected, whereas markers of apoptosis were increased in soleus muscle of THP-treated rats. In EDL muscle, carnitine depletion was associated with reduced free coenzyme A availability (Ϫ25%, P Ͻ 0.05), impaired peak tension development (Ϫ44%, P Ͻ 0.05), and increased glycogen hydrolysis (52%, P Ͻ 0.05) during muscle contraction, whereas PDC activation, muscle weight, and water content remained unaltered from CON. In conclusion, myopathy associated with carnitine deficiency can have different causes. Although muscle atrophy, most likely due to increased apoptosis, is predominant in muscle composed predominantly of type I fibers (soleus), disturbance of energy metabolism appears to be the major cause in muscle composed of type II fibers (EDL).N-trimethyl-hydrazine-3-propionate; secondary carnitine deficiency; carbohydrate metabolism; muscle atrophy; apoptosis CARNITINE IS A NATURALLY OCCURRING COMPOUND that is found in all mammalian tissues. L-Carnitine, the biologically effective isomer, plays a key role within several cellular energy producing pathways (9). For instance, carnitine is essential for the transport of long-chain fatty acids across the inner mitochondrial membrane toward their oxidative fate inside the mitochondrial matrix (15), is important for the removal of potentially toxic acyl-CoAs from the mitochondria by forming acylcarnitines (3, 6), and serves as a temporal acetyl group buffer in the oxidation of carbohydrates during periods of augmented pathway flux (14, 31).Fundamental to our understanding of the role of carnitine within the body is the ability to manipulate the size of the tissue carnitine pool and to investigate the consequences of such upon cellular, tissue, and whole body functions at rest and in response to external stresses such as muscular contraction. Although recent studies have shown that the skeletal muscle carnitine content can be increased in the presence of high circulating insulin concentrations by ϳ20% in humans (39,40,46), it appears to be more difficult to increa...

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

Cited by 46 publications

References 58 publications

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

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

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Contractile function and energy metabolism of skeletal muscle in rats with secondary carnitine deficiency

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