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

Abstract

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...

Vaccenic and Elaidic Acid Equally Esterify into Triacylglycerols, but Differently into Phospholipids of Fed Rat Liver Cells

“…These data may indicate that the expression levels of genes were increased with insulin, but without additional effects of isomers. Indeed, after various treatments, weakly higher or lower expression levels of the involved genes were found in fed animals [39][40][41][42]. Consequently, under this nutritional condition, the study of biochemical reactions related to TAG and PL synthesis appeared to be convenient to test the possible similarity of both trans-isomers through activity levels only depending on enzyme/substrate affinities.…”

The Regulation of Energy Metabolism Pathways Through L-Carnitine Homeostasis

“…Additionally, if the L-carnitine content is lowered significantly below the K m value of CPT I, a compensatory increase in CPT I expression is observed (Uenaka R 1996). After long-term mildronate treatment, a 2 to 2.5-fold increase in the expression of CPT IA and CPT IB was found in the heart and liver (Degrace et al, 2007;Liepinsh et al, 2008). However, the increase in CPT I protein expression cannot compensate for significantly reduced L-carnitine availability, and therefore, subsequent changes in metabolic pathways occur.…”

“…Several genes that are induced by mildronate treatment, particularly CPT I (Degrace et al, 2007;Liepinsh et al, 2008), suggest PPARs as possible nuclear factors involved in the mildronate-induced effects on glucose and FA metabolism (Fig. 4).…”

“…This delay could be because mildronate at doses up to 400 mg/kg did not affect the blood glucose concentration in non-diabetic rats. Mildronate reduced blood glucose in Wistar rats only at a dose of 800 mg (Degrace et al, 2007). The possible anti-diabetic effects of mildronate were then examined in an experimental model of type 2 diabetes in GK rats .…”

1296 Visceral Adipose Tissue Area as an Independent Risk Factor of Elevated Liver Enzyme in Nonalcoholic Fatty Liver Disease

“…Adipocytes in the visceral fat promote the increased release of free fatty acids and the subsequent production of cytokines, such as adiponectin, interleukin-6, tumor necrosis factor-a, and leptin, and these adipocytokines flow directly into the liver because abdominal fat has a circulatory communication pathway to the liver via the portal vein. [29][30][31] In addition, these adipocytokines have been known to induce insulin resistance and enhance hepatic steatosis, and they may also induce nonalcoholic steatohepatitis. 32 Furthermore, visceral fat was directly associated with hepatic inflammation and fibrosis in a dose-dependent manner, independent of insulin resistance.…”