LXRα regulates human CETP expression in vitro and in transgenic mice

Honzumi, Shoko; Shima, Akiko; Hiroshima, Ayano; Koieyama, Tadashi; Ubukata, Naoko; Terasaka, Naoki

doi:10.1016/j.atherosclerosis.2010.04.025

Cited by 38 publications

(36 citation statements)

References 46 publications

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“…Statins have been shown to increase ApoA-I protein and ABCA1 mRNA levels in hepatoma cell lines (16), but to reduce CETP activity (18). CETP mRNA was reported to be regulated by LXRα (30,31), whereas hepatic ABCA1 mRNA expression is regulated by SREBP2 as well as LXRα (19). In this study, we showed that pitavastatin raised total ABCA1 mRNA levels by increasing SREBP2-regulated type L ABCA1 mRNA levels, while decreasing type P ABCA1 mRNA expression by repressing LXR activity.…”

Section: Discussionmentioning

confidence: 58%

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

et al. 2011

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Abstract. Hepatic ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) production by apolipoprotein A-I (ApoA-I) lipidation. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, increase ABCA1 mRNA levels in hepatoma cell lines, but their mechanism of action is not yet clear. We investigated how statins increase ABCA1 in rat hepatoma McARH7777 cells. Pitavastatin, atorvastatin, and simvastatin increased total ABCA1 mRNA levels, whereas pravastatin had no effect. Pitavastatin also increased ABCA1 protein. Hepatic ABCA1 expression in rats is regulated by both liver X receptor (LXR) and sterol regulatory element-binding protein (SREBP2) pathways. Pitavastatin repressed peripheral type ABCA1 mRNA levels and its LXR-driven promoter, but activated the liver-type SREBPdriven promoter, and eventually increased total ABCA1 mRNA expression. Furthermore, pitavastatin increased peroxisome proliferator-activated receptor α (PPARα) and its downstream gene expression. Knockdown of PPARα attenuated the increase in ABCA1 protein, indicating that pitavastatin increased ABCA1 protein via PPARα activation, although it repressed LXR activation. Furthermore, the degradation of ABCA1 protein was retarded in pitavastatin-treated cells. These data suggest that pitavastatin increases ABCA1 protein expression by dual mechanisms: SREBP2-mediated mRNA transcription and PPARα-mediated ABCA1 protein stabilization, but not by the PPAR-LXR-ABCA1 pathway.

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Section: Discussionmentioning

confidence: 58%

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

et al. 2011

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“…In the case of LXR, several differences between mouse and human gene regulation have been described. For example, Cyp7A1 is a target of LXRs in mice but not humans, and the CETP gene is an LXR target that is not present in mice (Honzumi et al, 2010; Luo and Tall, 2000; Repa et al, 2000). To address the possibility of a species-specific regulation of IDOL, we compared the activity of the LXR–IDOL pathway in mice, humans, and cynomolgus monkeys.…”

Section: Resultsmentioning

confidence: 99%

The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

et al. 2014

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Summary The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR–IDOL axis are both tissue- and species-specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans.

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“…On a potency adjusted exposure basis, BMS-779788 was approximately 40-fold less potent than T0901317 in raising plasma TG and 17-fold less potent in LDL-C and apoB elevation after 7 days of treatment. In an earlier report, T0901317 was shown to increase plasma CETP activity in cynomolgus monkeys (Honzumi et al, 2010), consistent with CETP being an LXR target gene and an activity that is likely to play a significant role in LXR-dependent LDL-C elevations. As was the case with TG, LDL-C, apoB, BMS-779788 was also less potent in CETP mass elevation.…”

Section: Discussionmentioning

confidence: 89%

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

Kirchgessner

Martin

Sleph

et al. 2014

J Pharmacol Exp Ther

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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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LXRα regulates human CETP expression in vitro and in transgenic mice

Cited by 38 publications

References 46 publications

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

Pitavastatin Increases ABCA1 Expression by Dual Mechanisms: SREBP2-Driven Transcriptional Activation and PPARα-Dependent Protein Stabilization but Without Activating LXR in Rat Hepatoma McARH7777 Cells

The LXR–Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice

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

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