Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice

Peng, Dacheng; Hiipakka, Richard A.; Xie, Jing‐Tian; Reardon, Catherine A.; Getz, Godfrey S.; Liao, Shutsung

doi:10.1016/j.atherosclerosis.2009.07.016

Cited by 16 publications

(16 citation statements)

References 34 publications

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“…The cholesterol efflux transporters ABCG5 and ABCG8 were also modestly induced in liver, a result similar to the reported inductions in mouse by full pan agonists (Repa et al, 2002). Previous studies in mouse have shown an induction of lipoprotein lipase (LPL) in liver that could account for a blunting of elevated plasma TGs due to increased clearance of TG-rich lipoprotein particles (Zhang et al, 2001;Peng et al, 2010). In these studies, no effect of BMS-779788 on cynomolgus monkey hepatic LPL mRNA was observed, suggesting that this effect may not translate to higher species.…”

Section: Pharmacology Of a Novel Lxr Agonist In Nonhuman Primatessupporting

confidence: 68%

Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates

Kirchgessner

Martin

Sleph

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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Liver X Receptors (LXRs) a and b are nuclear hormone receptors that regulate multiple genes involved in reverse cholesterol transport (RCT) and are potential drug targets for atherosclerosis. However, full pan agonists also activate lipogenic genes, resulting in elevated plasma and hepatic lipids. We report the pharmacol-a potent partial LXR agonist with LXRb selectivity, which has an improved therapeutic window in the cynomolgus monkey compared with a full pan agonist. BMS-779788 induced LXR target genes in blood in vivo with an EC 50 5 610 nM, a value similar to its in vitro blood gene induction potency. BMS-779788 was 29-and 12-fold less potent than the full agonist T0901317 in elevating plasma triglyceride and LDL cholesterol, respectively, with similar results for plasma cholesteryl ester transfer protein and apolipoprotein B. However, ABCA1 and ABCG1 mRNA inductions in blood, which are critical for RCT, were comparable. Increased liver triglyceride was observed after 7-day treatment with BMS-779788 at the highest dose tested and was nearly identical to the dose response for plasma triglyceride, consistent with the central role of liver LXR in these lipogenic effects. Dose-dependent increases in biliary cholesterol and decreases in phospholipid and bile acid occurred in BMS-779788-treated animals, similar to LXR agonist effects reported in mouse. In summary, BMS-779788, a partial LXRb selective agonist, has decreased lipogenic potential compared with a full pan agonist in cynomolgus monkeys, with similar potency in the induction of genes known to stimulate RCT. This provides support in nonhuman primates for improving LXR agonist therapeutic windows by limiting LXRa activity.

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Section: Pharmacology Of a Novel Lxr Agonist In Nonhuman Primatessupporting

confidence: 68%

Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates

Kirchgessner

Martin

Sleph

et al. 2015

The Journal of Pharmacology and Experimental Therapeutics

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“…In both models there was both an increase in VLDL production and secretion and an increase in LPL production and activity in T0901317-treated animals. In wild-type mice, lipolysis and clearance predominates, while in the absence of LDLr, which plays a major role in the clearance of apoB-containing lipoproteins, increased output predominates 38) . The reduction of atherosclerotic lesions observed in the present study may be explained by factors other than the decrease in TC and TG, such as inflammation, endothelial dysfunction 31) , oxidative stress 37) and genetic factors.…”

Section: Discussionmentioning

confidence: 99%

“…Such accumulation in the serum is due to its lower clearance, since the half-life of this lipoprotein may be increased by up to 30-fold in LDLr −/− mice, as compared to wild animals 37) . For instance, Peng et al 38) examined the effect of longterm activation of hepatic nuclear receptor (LXR) on plasma TG homeostasis in wild-type C57BL/6 and LDLr −/− mice by treating these animals with the LXR…”

mentioning

confidence: 99%

Improvements of Atherosclerosis and Hepatic Oxidative Stress are Independent of Exercise Intensity in LDLr<sup>-/-</sup> Mice

Teodoro

Natali²,

Fernandes³

et al. 2012

J Atheroscler Thromb

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) and G3 (0.014±0.001 cm 2 ) presented lower aortic fat deposition than G1 (0.039±0.005 cm 2 ). G2 and G3 exhibited higher HDL-C, TG and CAT activity, but lower lipid peroxidation and carbonyl protein than G1. SOD values were higher in G3 than G2 and G1, and GPx was higher in G2 than in G3 and G1. Conclusions: Our protocols of low-and moderate-intensity aerobic exercise training (30 min daily for 8 weeks) induced similar benefits in LDLr −/− mice with atherosclerosis.J Atheroscler Thromb, 2012; 19:904-911.

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“…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: 87%

“…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.…”

mentioning

confidence: 99%

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

et al. 2014

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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...

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Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice

Cited by 16 publications

References 34 publications

Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates

Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates

Improvements of Atherosclerosis and Hepatic Oxidative Stress are Independent of Exercise Intensity in LDLr<sup>-/-</sup> Mice

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

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