LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

organism under different nutritional environments. This adaptation requires major changes in the hepatic metabolic gene program. One gene family, long-chain acyl-CoA synthetase (ACSL), encodes enzymes that play key roles in lipid metabolism in liver, as well as other metabolic tissues ( 1-5 ). ACSL catalyzes the formation of fatty acyl-CoA from ATP, CoA, and long-chain fatty acids (FAs). This reaction is the fi rst step in FA metabolism following transport of nonesterifi ed FA into mammalian cells. This activation process is essential for cellular utilization of FA via different metabolic pathways, including the cellular ␤ -oxidation system responsible for FA oxidation (catabolism) and the anabolic pathways for the synthesis of phospholipids, cholesterol esters, and triglycerides (TG). To date, fi ve isoforms of ACSL (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6) have been characterized in humans, mice, and rats ( 3 ). These isoforms differ considerably in their characteristics, including substrate specifi city, enzyme kinetics, and tissue and subcellular distribution. These individual characteristics contribute to their different cellular functions and metabolic outcomes (6)(7)(8)(9)(10)(11)(12)(13)(14). Because each isoform of the ACSL family has a distinct function in directing acyl-CoA to one or more specifi c downstream pathways, the level of expression/activity of individual ACSL isozymes could directly infl uence FA metabolic fates in liver tissue.Nutritional status and hormone levels differently affect the gene expression of ACSL family members in liver tissue ( 15-17 ). In mice fed a normal chow diet, fasting increased the mRNA abundance of ACSL4 and ACSL1 in the liver, and fasting decreased ACSL3 and ACSL5 mRNA levels. In liver of Wister rat, fasting had little effect on ACSL5 mRNA expression, but refeeding markedly increased Abstract Long-chain acyl-CoA synthetases (ACSL) play key roles in fatty acid metabolism in liver and other metabolic tissues in an isozyme-specifi c manner. In this study, we examined the effects of a fructose-enriched diet on expressions of ACSL isoforms in the liver of hamsters. We showed that the fructose diet markedly reduced the mRNA and protein expressions of ACSL3 in hamster liver without signifi cant effects on other ACSLs. The decrease in ACSL3 abundance was accompanied by a reduction in ACSL-catalyzed synthesis of arachidonyl-CoA and oleoyl-CoA in liver homogenates of hamsters fed the fructose diet as opposed to normal diet. We further showed that fructose diet specifically reduced expressions of three key components of the LXR signaling pathway, namely, liver X receptor (LXR) ␣ , LXR ␤ , and retinoid X receptor (RXR) ␤ . Exogenous expression and activation of LXR ␣ / ␤ increased hamster ACSL3 promoter activities in a LXR-responsive element (LXRE)-dependent fashion. Finally, we showed that treating hamsters with LXR agonist GW3965 increased hepatic ACSL3 expression without affecting other ACSL isoforms. Furthermore, the ligand-induced increases of ACSL3 expression were accompan...

show abstract

“…8A ). The effects of GW3965 on serum triglycerides have been previously reported in hamsters ( 40,41 ) and other rodent models ( 42 ).…”

Section: Effects Of Diet and Lxr Ligand Activation On Serum And Hepatmentioning

confidence: 99%

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

Dong

Kan

Singh

et al. 2013

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Hong et al suggested that LXR agonist raises plasma LDL cholesterol levels in primates, but not in mice, through activation of the LXR-regulated E3 ubiquitin axis. Another study from Quinet et al found that LXR ligand activation with the selective LXR agonist WAY-252623 lowers serum LDL cholesterol in cynomolgus monkeys, is neutral in Syrian hamsters, and reduces atherosclerosis in mouse (44). These results would question the relevance of ongoing efforts to target LXR in human diseases using rodent models.…”

Section: Lxr Function In Liver Lxr In Cholesterol Homeostasismentioning

confidence: 76%

Liver X receptors as regulators of metabolism

Korach-André

Gustafsson²

2015

Biomolecular Concepts

View full text Add to dashboard Cite

Abstract:The liver X receptors (LXR) are crucial regulators of metabolism. After ligand binding, they regulate gene transcription and thereby mediate changes in metabolic pathways. Modulation of LXR and their downstream targets has appeared to be a promising treatment for metabolic diseases especially atherosclerosis and cholesterol metabolism. However, the complexity of LXR action in various metabolic tissues and the liver side effect of LXR activation have slowed down the interest for LXR drugs. In this review, we summarized the role of LXR in the main metabolically active tissues with a special focus on obesity and associated diseases in mammals. We will also discuss the dual interplay between the two LXR isoforms suggesting that they may collaborate to establish a fine and efficient system for the maintenance of metabolism homeostasis.

show abstract

“…Previous studies have shown increased VLDL-TG production or have provided circumstantial evidence for enhanced VLDL-TG clearance on LXR activation (4,14), whereas conflicting effects on circulating TG levels have been reported (4,11,(13)(14)(15). Application of ADAPT resolved this apparent inconsistency, as it revealed that VLDL-TG secretion predominates during the early response to LXR agonism, thereby initially invoking elevated VLDL-TG concentrations.…”

Section: Discussionmentioning

confidence: 86%

“…Published data on the effects of pharmacologic LXR agonism on plasma VLDL-TG levels indicate transient effects in rodents and nonhuman primates (4,11,(13)(14)(15). The mechanistic basis of these temporal changes in plasma TG levels is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation

et al. 2014

View full text Add to dashboard Cite

Liver X receptor (LXR) agonists exert potent antiatherosclerotic actions but simultaneously induce excessive triglyceride (TG) accumulation in the liver. To obtain a detailed insight into the underlying mechanism of hepatic TG accumulation, we used a novel computational modeling approach called analysis of dynamic adaptations in parameter trajectories (ADAPT). We revealed that both input and output fluxes to hepatic TG content are considerably induced on LXR activation and that in the early phase of LXR agonism, hepatic steatosis results from only a minor imbalance between the two. It is generally believed that LXR-induced hepatic steatosis results from increased de novo lipogenesis (DNL). In contrast, ADAPT predicted that the hepatic influx of free fatty acids is the major contributor to hepatic TG accumulation in the early phase of LXR activation. Qualitative validation of this prediction showed a 5-fold increase in the contribution of plasma palmitate to hepatic monounsaturated fatty acids on acute LXR activation, whereas DNL was not yet significantly increased. This study illustrates that complex effects of pharmacological intervention can be translated into distinct patterns of metabolic regulation through state-ofthe-art mathematical modeling.-Hijmans, B. S., Tiemann, C. A., Grefhorst, A., Boesjes, M., van Dijk, T. H., Tietge, U. J. F., Kuipers, F., van Riel, N. A. W., Groen, A. K., Oosterveer, M. H. A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation. FASEB J. 29, 1153-1164 (2015). www.fasebj.org Key Words: computational modeling • T0901317 • fatty liver • FFA flux • VLDL metabolism LIVER X RECEPTORS (LXRS) are transcription factors that play a central role in the regulation of lipid and carbohydrate metabolism (1). Under physiologic conditions, LXRs are activated by oxygenated metabolites of cholesterol (2). Because LXR agonism raises plasma HDL levels (3, 4), potently promotes cholesterol excretion (5, 6), and reduces atherosclerotic plaque formation in rodent models (7), LXR is considered an attractive drug target for antiatherosclerotic therapies (8, 9). LXR agonists, however, also cause severe hepatic triglyceride (TG) accumulation in animal models (3,4). This has been attributed to transcriptional up-regulation of lipogenic genes (10, 11) and subsequent stimulation of de novo lipogenesis (DNL) in the liver. The induction of hepatic steatosis is a major drawback for the clinical application of LXR agonists because this condition may predispose to the development of nonalcoholic steatohepatitis and eventually hepatocarcinoma (12).Increases in hepatic TG synthesis and content on pharmacological LXR activation are generally believed to be driving forces for the secretion of large, TG-rich very lowdensity lipoprotein (VLDL) particles by the liver (4). Published data on the effects of pharmacologic LXR agonism on plasma VLDL-TG levels indicate transient effects in rodents and nonhuman primates (4,11,(13)(14)(15). The mechanistic b...

show abstract

LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse

Cited by 90 publications

References 40 publications

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

High-fructose diet downregulates long-chain acyl-CoA synthetase 3 expression in liver of hamsters via impairing LXR/RXR signaling pathway

Liver X receptors as regulators of metabolism

A systems biology approach reveals the physiological origin of hepatic steatosis induced by liver X receptor activation

Contact Info

Product

Resources

About