Synthetic LXR agonist inhibits the development of atherosclerosis in New Zealand White rabbits

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

doi:10.1016/j.bbalip.2011.08.009

Cited by 21 publications

(13 citation statements)

References 39 publications

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“…Additionally, it has been shown that LXRs also possess potent anti‐inflamatory effects, in both cultured macrophages and living mice (Joseph et al ., ), that should further boost LXR anti‐atherogenic potential. Different lines of evidence strongly suggest that LXR activation might indeed be an excellent therapy for atherosclerosis: first, LXR activation with the nonsteroidal LXR agonist GW3965 significantly decreases plaque lesion surface in atherosclerosis‐prone mouse models (Joseph et al ., ); second, macrophage‐specific deficiency of both LXR isoforms in mice (LXRαβ −/− ) significantly aggravates atherosclerotic aortic lesions in hypercholesterolemic mice (Tangirala et al ., ); and third, LXR activation promotes reverse‐cholesterol transport and faecal net elimination of cholesterol in dyslipidemic hamsters (Briand et al ., ) and rabbits (Honzumi et al ., ), two models of lipid metabolism and atherosclerosis more similar to human physiology than mice.…”

Section: Cholesterol Physiological Regulation and Pathological Implicmentioning

confidence: 99%

Retracted: Advances in the physiological and pathological implications of cholesterol

et al. 2013

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Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco- and mineralo-corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high-impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol-related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades.

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Section: Cholesterol Physiological Regulation and Pathological Implicmentioning

confidence: 99%

Retracted: Advances in the physiological and pathological implications of cholesterol

et al. 2013

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“…18 However, development of LXR agonists has been hampered by their induction of hepatic steatosis, which might be because of increased fatty acid biosynthesis via increased expression of SREBP1-c. 18 Besides, LXR agonists might also raise LDL-C levels. In this regard, Honzumi et al 19 reported that administration of a synthetic LXR ligand, TO0901317, increased LDL-C levels at a dose that did not affect triglyceride levels in rabbits. They did not assess Idol and PCSK9 expressions but TO0901317 may enhance them.…”

mentioning

confidence: 99%

Hepatic Overexpression of Idol Increases Circulating Protein Convertase Subtilisin/Kexin Type 9 in Mice and Hamsters via Dual Mechanisms

Sasaki

Terao

Ayaori

et al. 2014

ATVB

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Objective— Low-density lipoprotein receptor (LDLR) is degraded by inducible degrader of LDLR (Idol) and protein convertase subtilisin/kexin type 9 (PCSK9), thereby regulating circulating LDL levels. However, it remains unclear whether, and if so how, these LDLR degraders affect each other. We therefore investigated effects of liver-specific expression of Idol on LDL/PCSK9 metabolism in mice and hamsters. Approach and Results— Injection of adenoviral vector expressing Idol (Ad-Idol) induced a liver-specific reduction in LDLR expression which, in turn, increased very-low-density lipoprotein/LDL cholesterol levels in wild-type mice because of delayed LDL catabolism. Interestingly, hepatic Idol overexpression markedly increased plasma PCSK9 levels. In LDLR-deficient mice, plasma PCSK9 levels were already elevated at baseline and unchanged by Idol overexpression, which was comparable with the observation for Ad-Idol–injected wild-type mice, indicating that Idol-induced PCSK9 elevation depended on LDLR. In wild-type mice, but not in LDLR-deficient mice, Ad-Idol enhanced hepatic PCSK9 expression, with activation of sterol regulatory element–binding protein 2 and subsequently increased expression of its target genes. Supporting in vivo findings, Idol transactivated PCSK9/LDLR in sterol regulatory element–binding protein 2/LDLR-dependent manners in vitro. Furthermore, an in vivo kinetic study using 125 I-labeled PCSK9 revealed delayed clearance of circulating PCSK9, which could be another mechanism. Finally, to extend these findings into cholesteryl ester transfer protein–expressing animals, we repeated the above in vivo experiments in hamsters and obtained similar results. Conclusions— A vicious cycle in LDLR degradation might be generated by PCSK9 induced by hepatic Idol overexpression via dual mechanisms: sterol regulatory element–binding protein 2/LDLR. Furthermore, these effects would be independent of cholesteryl ester transfer protein expression.

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“…This is explained by the CETP-mediated transfer of cholesterol from HDL to apoB-containing lipoproteins. Interestingly, the lack of increase in HDL cholesterol concentration did not affect the ability of LXR agonists to stimulate reverse cholesterol transport from macrophages suggesting that LXR agonists are still atheroprotective in the presence of CETP [6], [22]. In the quest of other easily accessible biomarkers of LXR activity some groups, including our, proposed that peripheral blood monocytes could be useful to monitor LXR activation [25], [26].…”

Section: Introductionmentioning

confidence: 99%

“…First studies in the mouse suggested that changes in lipoprotein profile could be useful to monitor LXR activation. Indeed LXR agonists increase HDL cholesterol in a dose dependent manner in the mouse [20]–[22]. However, unlike human, the mouse is a CETP-deficient species and subsequent studies in CETP transgenic mice, rabbits and primates clearly demonstrated that LXR agonists do not increase plasma HDL concentration in the presence of CETP [22]–[24].…”

Section: Introductionmentioning

confidence: 99%

Identification of Biological Markers of Liver X Receptor (LXR) Activation at the Cell Surface of Human Monocytes

et al. 2012

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BackgroundLiver X receptor (LXR) α and LXR β (NR1H3 and NR1H2) are oxysterol-activated nuclear receptors involved in the control of major metabolic pathways such as cholesterol homeostasis, lipogenesis, inflammation and innate immunity. Synthetic LXR agonists are currently under development and could find applications in various fields such as cardiovascular diseases, cancer, diabetes and neurodegenerative diseases. The clinical development of LXR agonists requires the identification of biological markers for pharmacodynamic studies. In this context, monocytes represent an attractive target to monitor LXR activation. They are easily accessible cells present in peripheral blood; they express LXR α and β and respond to LXR agonist stimulation in vitro. The aim of our study was to identify cell surface markers of LXR agonists on monocytes. For this, we focused on clusters of differentiation (CD) markers because they are well characterized and accessible cell surface molecules allowing easy immuno-phenotyping.Methodology/Principal FindingsBy using microarray analysis of monocytes treated or not with an LXR agonist in vitro, we selected three CD, i.e. CD82, CD226, CD244 for further analysis by real time PCR and flow cytometry. The three CD were up-regulated by LXR agonist treatment in vitro in a time- and dose- dependent manner and this induction was LXR specific as assessed by a SiRNA or LXR antagonist strategy. By using flow cytometry, we could demonstrate that the expression of these molecules at the cell surface of monocytes was significantly increased after LXR agonist treatment.Conclusions/SignificanceWe have identified three new cell surface markers that could be useful to monitor LXR activation. Future studies will be required to confirm the biological and diagnostic significance of the markers.

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Synthetic LXR agonist inhibits the development of atherosclerosis in New Zealand White rabbits

Cited by 21 publications

References 39 publications

Retracted: Advances in the physiological and pathological implications of cholesterol

Retracted: Advances in the physiological and pathological implications of cholesterol

Hepatic Overexpression of Idol Increases Circulating Protein Convertase Subtilisin/Kexin Type 9 in Mice and Hamsters via Dual Mechanisms

Identification of Biological Markers of Liver X Receptor (LXR) Activation at the Cell Surface of Human Monocytes

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