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Elma Aflaki,
Branislav Radovic, Prakash G Chandak,
Dagmar Kolb,
Tobias Eisenberg,
Julia Ring,
Ismene Fertschai,
Andreas Uellen,
Heimo Wolinski,
Sepp-Dieter Kohlwein,
Rudolf Zechner,
Sanja Levak-Frank,
Wolfgang Sattler,
Wolfgang F Graier,
Roland Malli,
Frank Madeo,
Dagmar Kratky
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Marlene Buchebner,
Thomas Pfeifer,
Nora Rathke, Prakash G Chandak,
Achim Lass,
Renate Schreiber,
Adelheid Kratzer,
Robert Zimmermann,
Wolfgang Sattler,
Harald Koefeler,
Eleonore Fröhlich,
Gerhard M Kostner,
Ruth Birner-Gruenberger,
Kyle P Chiang,
Guenter Haemmerle,
Rudolf Zechner,
Sanja Levak-Frank,
Benjamin Cravatt,
Dagmar Kratky
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Adelheid Kratzer,
Marlene Buchebner,
Thomas Pfeifer,
Tatjana M Becker,
Georg Uray,
Makoto Miyazaki,
Shinobu Miyazaki-Anzai,
Birgit Ebner, Prakash G Chandak,
Rajendra S Kadam, [......],
Helmut Ahammer,
Branislav Radovic,
Michael Trauner,
Gerald Hoefler,
Uday B Kompella,
Guenter Fauler,
Moshe Levi,
Sanja Levak-Frank,
Gerhard M Kostner,
Dagmar Kratky
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Elma Aflaki,
Nariman A B Balenga,
Petra Luschnig-Schratl,
Heimo Wolinski,
Silvia Povoden, Prakash G Chandak,
Juliane G Bogner-Strauss,
Sandra Eder,
Viktoria Konya,
Sepp-Dieter Kohlwein,
Akos Heinemann,
Dagmar Kratky
Cellular and Molecular Life Sciences CMLS 05/2013; · 6.57 Impact Factor
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Prakash Doddapattar,
Branislav Radović,
Jay V Patankar,
Sascha Obrowsky,
Katharina Jandl,
Christoph Nusshold,
Dagmar Kolb,
Nemanja Vujić,
Lalit Doshi, Prakash G Chandak,
Madeleine Goeritzer,
Helmut Ahammer,
Gerald Hoefler,
Wolfgang Sattler,
Dagmar Kratky
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ABSTRACT: SCOPE: Xanthohumol (XN), a prenylated antioxidative and anti-inflammatory chalcone from hops, exhibits positive effects on lipid and glucose metabolism. Based on its favorable biological properties, we investigated whether XN attenuates atherosclerosis in western-type diet-fed apolipoprotein-E-deficient (ApoE(-/-) ) mice. METHODS AND RESULTS: XN supplementation markedly reduced plasma cholesterol concentrations, decreased atherosclerotic lesion area, and attenuated plasma concentrations of the proinflammatory cytokine monocyte chemoattractant protein 1. Decreased hepatic triglyceride and cholesterol content, activation of AMP-activated protein kinase, phosphorylation and inactivation of acetyl-CoA carboxylase, and reduced expression levels of mature sterol regulatory element-binding protein (SREBP)-2 and SREBP-1c mRNA indicate reduced lipogenesis in the liver of XN-fed ApoE(-/-) mice. Concomitant induction of hepatic mRNA expression of carnitine palmitoyltransferase-1a in ApoE(-/-) mice-administered XN suggests increased fatty acid beta-oxidation. Fecal cholesterol concentrations were also markedly increased in XN-fed ApoE(-/-) mice compared with mice fed western-type diet alone. CONCLUSION: The atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase.
Molecular Nutrition & Food Research 05/2013; · 4.30 Impact Factor
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ABSTRACT: Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triglyceride (TG) hydrolysis. The lack of ATGL results in TG accumulation in multiple tissues, underscoring the critical role of ATGL in maintaining lipid homeostasis. Recent evidence suggests that ATGL affects TG metabolism via activation of peroxisome proliferator-activated receptor alpha (PPARα). To investigate specific effects of intestinal ATGL on lipid metabolism we generated mice lacking ATGL exclusively in the intestine (ATGLiKO). We found decreased TG hydrolase activity and increased intracellular TG content in ATGLiKO small intestines. Intragastric administration of [3H]trioleate resulted in the accumulation of radioactive TG in the intestine, whereas absorption into the systemic circulation was unchanged. Intraperitoneally injected [3H]oleate also accumulated within TG in ATGLiKO intestines, indicating that ATGL mobilizes fatty acids from the systemic circulation absorbed by the basolateral side from the blood. Downregulation of PPARα target genes suggested modulation of cholesterol absorption by intestinal ATGL. Accordingly, ATGL deficiency in the intestine resulted in delayed cholesterol absorption. Importantly, this study provides evidence that ATGL has no impact on intestinal TG absorption but hydrolyzes TGs taken up from the intestinal lumen and systemic circulation. Our data support the role of ATGL in modulating PPARα-dependent processes also in the small intestine.
The Journal of Lipid Research 12/2012; · 5.56 Impact Factor
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ABSTRACT: Hormone sensitive lipase (HSL) regulates the hydrolysis of acylglycerols and cholesteryl esters (CE) in various cells and organs, including enterocytes of the small intestine. The physiological role of this enzyme in enterocytes, however, stayed elusive. In the present study we generated mice lacking HSL exclusively in the small intestine (HSLiKO) to investigate the impact of HSL deficiency on intestinal lipid metabolism and the consequences on whole body lipid homeostasis. Chow diet-fed HSLiKO mice showed unchanged plasma lipid concentrations. In addition, feeding with high fat/high cholesterol (HF/HC) diet led to unaltered triglyceride but increased plasma cholesterol concentrations and CE accumulation in the small intestine. The same effect was observed after an acute cholesterol load. Gavaging of radioactively labeled cholesterol resulted in increased abundance of radioactivity in plasma, liver and small intestine of HSLiKO mice 4h post-gavaging. However, cholesterol absorption determined by the fecal dual-isotope ratio method revealed no significant difference, suggesting that HSLiKO mice take up the same amount of cholesterol but in an accelerated manner. mRNA expression levels of genes involved in intestinal cholesterol transport and esterification were unchanged but we observed downregulation of HMG-CoA reductase and synthase and consequently less intestinal cholesterol biosynthesis. Taken together our study demonstrates that the lack of intestinal HSL leads to CE accumulation in the small intestine, accelerated cholesterol absorption and decreased cholesterol biosynthesis, indicating that HSL plays an important role in intestinal cholesterol homeostasis.
Biochimica et Biophysica Acta 07/2012; 1821(11):1406-14. · 4.66 Impact Factor
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Prakash G Chandak,
Sascha Obrowsky,
Branislav Radovic,
Prakash Doddapattar,
Elma Aflaki,
Adelheid Kratzer,
Lalit S Doshi,
Silvia Povoden,
Helmut Ahammer,
Gerald Hoefler,
Sanja Levak-Frank,
Dagmar Kratky
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ABSTRACT: Triacylglycerols (TG) are the major storage molecules of metabolic energy and fatty acids in several tissues. The final step in TG biosynthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Lack of whole body DGAT1 is associated with reduced lipid-induced inflammation. Since one major component of atherosclerosis is chronic inflammation we hypothesized that DGAT1 deficiency might ameliorate atherosclerotic lesion development. We therefore crossbred Apolipoprotein E-deficient (ApoE(-/-)) mice with Dgat1(-/-) mice. ApoE(-/-) and ApoE(-/-)Dgat1(-/-) mice were fed Western-type diet (WTD) for 9weeks and thereafter examined for plaque formation. The mean atherosclerotic lesion area was substantially reduced in ApoE(-/-)Dgat1(-/-) compared with ApoE(-/-) mice in en face and aortic valve section analyses. The reduced lesion size was associated with decreased cholesterol uptake and absorption by the intestine, reduced plasma TG and cholesterol concentrations and increased cholesterol efflux from macrophages. The expression of adhesion molecules was reduced in aortas of ApoE(-/-)Dgat1(-/-) mice, which might be the reason for less migration capacities of monocytes and macrophages and the observed decreased amount of macrophages within the plaques. From our results we conclude that the lack of DGAT1 is atheroprotective, implicating an additional application of DGAT1 inhibitors with regard to maintaining cholesterol homeostasis and attenuating atherosclerosis.
Biochimica et Biophysica Acta 09/2011; 1811(12):1011-20. · 4.66 Impact Factor
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Elma Aflaki,
Nariman A B Balenga,
Petra Luschnig-Schratl,
Heimo Wolinski,
Silvia Povoden, Prakash G Chandak,
Juliane G Bogner-Strauss,
Sandra Eder,
Viktoria Konya,
Sepp-Dieter Kohlwein,
Akos Heinemann,
Dagmar Kratky
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ABSTRACT: Infiltration of monocytes and macrophages into the site of inflammation is critical in the progression of inflammatory diseases such as atherosclerosis. Cell migration is dependent on the continuous organization of the actin cytoskeleton, which is regulated by members of the small Rho GTPase family (RhoA, Cdc42, Rac) that are also important for the regulation of signal transduction pathways. We have recently reported on reduced plaque formation in an atherosclerotic mouse model transplanted with bone marrow from adipose triglyceride lipase-deficient (Atgl-/-) mice. Here we provide evidence that defective lipolysis in macrophages lacking ATGL, the major enzyme responsible for triacylglycerol hydrolysis, favors an anti-inflammatory M2-like macrophage phenotype. Our data implicate an as yet unrecognized principle that insufficient lipolysis influences macrophage polarization and actin polymerization, resulting in impaired macrophage migration. Sustained phosphorylation of focal adhesion kinase [due to inactivation of its phosphatase by elevated levels of reactive oxygen species (ROS)] results in defective Cdc42, Rac1 and RhoA activation and in increased and sustained activation of Rac2. Inhibition of ROS production restores the migratory capacity of Atgl-/- macrophages. Since monocyte and macrophage migration are a prerequisite for infiltrating the arterial wall, our results provide a molecular link between lipolysis and the development of atherosclerosis.
Cellular and Molecular Life Sciences CMLS 05/2011; 68(23):3933-47. · 6.57 Impact Factor
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Thomas Pfeifer,
Marlene Buchebner, Prakash G Chandak,
Jay Patankar,
Adelheid Kratzer,
Sascha Obrowsky,
Gerald N Rechberger,
Rajendra S Kadam,
Uday B Kompella,
Gerhard M Kostner,
Dagmar Kratky,
Sanja Levak-Frank
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ABSTRACT: The liver X receptors (LXRs) are key regulators of genes involved in cholesterol homeostasis. Natural ligands and activators of LXRs are oxysterols. Numerous steroidal and non-steroidal synthetic LXR ligands are under development as potential drugs for individuals suffering from lipid disorders. N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is a steroidal ligand of LXRs that exerts anti-atherogenic effects in apolipoprotein E-deficient mice without causing negative side effects such as liver steatosis or hypertriglyceridemia. In this report, we investigated the consequences of DMHCA treatment on cholesterol homeostasis in vivo and in vitro. Despite its hydrophobicity, DMHCA is readily absorbed by C57BL/6 mice and taken up by intestinal cells, the lung, heart and kidneys, but is undetectable in the brain. DMHCA significantly reduces cholesterol absorption and uptake in duodenum and jejunum of the small intestine and in turn leads to a reduction of plasma cholesterol by 24%. The most striking finding of this study is that DMHCA inhibited the enzyme 3β-hydroxysterol-Δ24-reductase resulting in an accumulation of desmosterol in the plasma and in feces. Thus, the reduction of plasma cholesterol was due to a block in the final step of cholesterol biosynthesis. Taken together, DMHCA is an interesting compound with properties distinct from other LXR ligands and might be used to study desmosterol-mediated effects in cells and tissues.
Current pharmaceutical biotechnology 02/2011; 12(2):285-92. · 3.40 Impact Factor
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Elma Aflaki,
Branislav Radovic, Prakash G Chandak,
Dagmar Kolb,
Tobias Eisenberg,
Julia Ring,
Ismene Fertschai,
Andreas Uellen,
Heimo Wolinski,
Sepp-Dieter Kohlwein,
Rudolf Zechner,
Sanja Levak-Frank,
Wolfgang Sattler,
Wolfgang F Graier,
Roland Malli,
Frank Madeo,
Dagmar Kratky
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ABSTRACT: Programmed cell death of lipid-laden macrophages is a prominent feature of atherosclerotic lesions and mostly ascribed to accumulation of excess intracellular cholesterol. The present in vitro study investigated whether intracellular triacylglycerol (TG) accumulation could activate a similar apoptotic response in macrophages. To address this question, we utilized peritoneal macrophages isolated from mice lacking adipose triglyceride lipase (ATGL), the major enzyme responsible for TG hydrolysis in multiple tissues. In Atgl(-/-) macrophages, we observed elevated levels of cytosolic Ca(2+) and reactive oxygen species, stimulated cytochrome c release, and nuclear localization of apoptosis-inducing factor. Fragmented mitochondria prior to cell death were indicative of the mitochondrial apoptosis pathway being triggered as a consequence of defective lipolysis. Other typical markers of apoptosis, such as externalization of phosphatidylserine in the plasma membrane, caspase 3 and poly(ADP-ribose) polymerase cleavage, were increased in Atgl(-/-) macrophages. An artificial increase of cellular TG levels by incubating wild-type macrophages with very low density lipoprotein closely mimicked the apoptotic phenotype observed in Atgl(-/-) macrophages. Results obtained during the present study define a novel pathway linking intracellular TG accumulation to mitochondrial dysfunction and programmed cell death in macrophages.
Journal of Biological Chemistry 01/2011; 286(9):7418-28. · 4.77 Impact Factor
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Jay V Patankar, Prakash G Chandak,
Sascha Obrowsky,
Thomas Pfeifer,
Clemens Diwoky,
Andreas Uellen,
Wolfgang Sattler,
Rudolf Stollberger,
Gerald Hoefler,
Akos Heinemann,
Michele Battle,
Stephen Duncan,
Dagmar Kratky,
Sanja Levak-Frank
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ABSTRACT: Transcriptional regulation of small intestinal gene expression controls plasma total cholesterol (TC) and triglyceride (TG) levels, which are major determinants of metabolic diseases. GATA4, a zinc finger domain transcription factor, is critical for jejunal identity, and intestinal GATA4 deficiency leads to a jejunoileal transition. Although intestinal GATA4 ablation is known to misregulate jejunal gene expression, its pathophysiological impact on various components of metabolic syndrome remains unknown. Here, we used intestine-specific GATA4 knockout (GATA4iKO) mice to dissect the contribution of GATA4 on obesity development. We challenged adult GATA4iKO mice and control littermates with a Western-type diet (WTD) for 20 wk. Our findings show that WTD-fed GATA4iKO mice are resistant to diet-induced obesity. Accordingly, plasma TG and TC levels are markedly decreased. Intestinal lipid absorption in GATA4iKO mice was strongly reduced, whereas luminal lipolysis was unaffected. GATA4iKO mice displayed a greater glucagon-like peptide-1 (GLP-1) release on normal chow and even after long-term challenge with WTD remained glucose sensitive. In summary, our findings show that the absence of intestinal GATA4 has a beneficial effect on decreasing intestinal lipid absorption causing resistance to hyperlipidemia and obesity. In addition, we show that increased GLP-1 release in GATA4iKO mice decreases the risk for development of insulin resistance.
AJP Endocrinology and Metabolism 12/2010; 300(3):E478-88. · 4.75 Impact Factor
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Marlene Buchebner,
Thomas Pfeifer,
Nora Rathke, Prakash G Chandak,
Achim Lass,
Renate Schreiber,
Adelheid Kratzer,
Robert Zimmermann,
Wolfgang Sattler,
Harald Koefeler,
Eleonore Fröhlich,
Gerhard M Kostner,
Ruth Birner-Gruenberger,
Kyle P Chiang,
Guenter Haemmerle,
Rudolf Zechner,
Sanja Levak-Frank,
Benjamin Cravatt,
Dagmar Kratky
[show abstract]
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ABSTRACT: Cholesteryl ester (CE) accumulation in macrophages represents a crucial event during foam cell formation, a hallmark of atherogenesis. Here we investigated the role of two previously described CE hydrolases, hormone-sensitive lipase (HSL) and KIAA1363, in macrophage CE hydrolysis. HSL and KIAA1363 exhibited marked differences in their abilities to hydrolyze CE, triacylglycerol (TG), diacylglycerol (DG), and 2-acetyl monoalkylglycerol ether (AcMAGE), a precursor for biosynthesis of platelet-activating factor (PAF). HSL efficiently cleaved all four substrates, whereas KIAA1363 hydrolyzed only AcMAGE. This contradicts previous studies suggesting that KIAA1363 is a neutral CE hydrolase. Macrophages of KIAA1363(-/-) and wild-type mice exhibited identical neutral CE hydrolase activity, which was almost abolished in tissues and macrophages of HSL(-/-) mice. Conversely, AcMAGE hydrolase activity was diminished in macrophages and some tissues of KIAA1363(-/-) but unchanged in HSL(-/-) mice. CE turnover was unaffected in macrophages lacking KIAA1363 and HSL, whereas cAMP-dependent cholesterol efflux was influenced by HSL but not by KIAA1363. Despite decreased CE hydrolase activities, HSL(-/-) macrophages exhibited CE accumulation similar to wild-type (WT) macrophages. We conclude that additional enzymes must exist that cooperate with HSL to regulate CE levels in macrophages. KIAA1363 affects AcMAGE hydrolase activity but is of minor importance as a direct CE hydrolase in macrophages.
The Journal of Lipid Research 10/2010; 51(10):2896-908. · 5.56 Impact Factor
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Bart Lammers, Prakash G Chandak,
Elma Aflaki,
Gijs H M Van Puijvelde,
Branislav Radovic,
Reeni B Hildebrand,
Illiana Meurs,
Ruud Out,
Johan Kuiper,
Theo J C Van Berkel,
Dagmar Kolb,
Guenter Haemmerle,
Rudolf Zechner,
Sanja Levak-Frank,
Miranda Van Eck,
Dagmar Kratky
[show abstract]
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ABSTRACT: The consequences of macrophage triglyceride (TG) accumulation on atherosclerosis have not been studied in detail so far. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme for the initial step in TG hydrolysis. Because ATGL knockout (KO) mice exhibit massive TG accumulation in macrophages, we used ATGL KO mice to study the effects of macrophage TG accumulation on atherogenesis.
Low-density lipoprotein receptor (LDLr) KO mice were transplanted with bone marrow from ATGL KO (ATGL KO→LDLr KO) or wild-type (WT→LDLr KO) mice and challenged with a Western-type diet for 9 weeks. Despite TG accumulation in ATGL KO macrophages, atherosclerosis in ATGL KO→LDLr KO mice was 43% reduced associated with decreased plasma monocyte chemoattractant protein-1 (MCP-1) and macrophage interleukin-6 concentrations. This coincided with a reduced amount of macrophages, possibly because of a 39% increase in intraplaque apoptosis and a decreased migratory capacity of ATGL KO macrophages. The reduced number of white blood cells might be due to a 36% decreased Lin(-)Sca-1(+)cKit(+) hematopoietic stem cell population.
We conclude that the attenuation of atherogenesis in ATGL KO→LDLr KO mice is due to decreased infiltration of less inflammatory macrophages into the arterial wall and increased macrophage apoptosis.
Arteriosclerosis Thrombosis and Vascular Biology 10/2010; 31(1):67-73. · 6.37 Impact Factor
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Prakash G Chandak,
Branislav Radovic,
Elma Aflaki,
Dagmar Kolb,
Marlene Buchebner,
Eleonore Fröhlich,
Christoph Magnes,
Frank Sinner,
Guenter Haemmerle,
Rudolf Zechner,
Ira Tabas,
Sanja Levak-Frank,
Dagmar Kratky
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ABSTRACT: Macrophage phagocytosis is an essential biological process in host defense and requires large amounts of energy. To date, glucose is believed to represent the prime substrate for ATP production in macrophages. To investigate the relative contribution of free fatty acids (FFAs) in this process, we determined the phagocytosis rates in normal mouse macrophages and macrophages of adipose triglyceride lipase (ATGL)-deficient mice. ATGL was shown to be the rate-limiting enzyme for the hydrolysis of lipid droplet-associated triacylglycerol (TG) in many tissues. Here, we demonstrate that Atgl(-/-) macrophages fail to efficiently hydrolyze cellular TG stores leading to decreased cellular FFA concentrations and concomitant accumulation of lipid droplets, even in the absence of exogenous lipid loading. The reduced availability of FFAs results in decreased cellular ATP concentrations and impaired phagocytosis suggesting that fatty acids must first go through a cycle of esterification and re-hydrolysis before they are available as energy substrate. Exogenously added glucose cannot fully compensate for the phagocytotic defect in Atgl(-/-) macrophages. Hence, phagocytosis was also decreased in vivo when Atgl(-/-) mice were challenged with bacterial particles. These findings imply that phagocytosis in macrophages depends on the availability of FFAs and that ATGL is required for their hydrolytic release from cellular TG stores. This novel mechanism links ATGL-mediated lipolysis to macrophage function in host defense and opens the way to explore possible roles of ATGL in immune response, inflammation, and atherosclerosis.
Journal of Biological Chemistry 06/2010; 285(26):20192-201. · 4.77 Impact Factor
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Rathinasabapathy Anandharajan,
Sufyan G Sayyed,
Lalit S Doshi,
Pooja Dixit, Prakash G Chandak,
Amol V Dixit,
Manoja K Brahma,
Nitin J Deshmukh,
Ravindra Gupte,
Anagha Damre,
Jaspreet Suthar,
Muralidhara Padigaru,
Somesh D Sharma,
Kumar V S Nemmani
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ABSTRACT: Insulin resistance is central to the pathogenesis of type 2 diabetes mellitus. Previous studies have demonstrated that compounds that cause adipogenesis and improve glucose uptake in 3T3-L1 cells are potential insulin sensitizers. Therefore, we evaluated one such compound, 18F9, for (1) adipogenesis in human subcutaneous preadipocyte (SQ) cells, (2) glucose uptake in human skeletal muscle myotubes and SQ cells, and (3) antidiabetic activity in db/db mice. We also investigated its effect on ex vivo glucose uptake in soleus muscle isolated from continuously treated db/db mice. Gene expression profiling in soleus muscle and epididymal fat of db/db mice was performed to understand its effect on glucose metabolism, lipid metabolism, and thermogenesis. 18F9 enhanced adipogenesis in SQ cells and increased glucose uptake in SQ and human skeletal muscle myotubes cells. In db/db mice, 18F9 exhibited dose-dependent reduction in plasma glucose and insulin level. Interestingly, 18F9 was as efficacious as rosiglitazone but did not cause body weight gain and hepatic adverse effects. In addition, 18F9 demonstrated no change in plasma volume in Wistar rats. Furthermore, it enhanced ex vivo glucose uptake in soleus muscles in these mice, which substantiates our in vitro findings. Human peroxisome proliferator activated receptor-gamma transactivation assay revealed a weak peroxisome proliferator activated receptor-gamma transactivation potential (44% of rosiglitazone at 10 mumol/L) of 18F9. Gene expression profiling indicated that 18F9 increased insulin sensitivity mainly through a phosphoinositide 3-kinase-dependent mechanism. 18F9 also up-regulated genes involved in lipid transport and synthesis at par with rosiglitazone. Unlike rosiglitazone, 18F9 elevated the expression of Pdk4. In addition, 18F9 elevated the expression of glycogen synthase and adiponectin significantly higher than rosiglitazone. Taken together, these observations suggest that 18F9 is a safer and potent insulin sensitizer that demonstrates promising antidiabetic activity and is worth further development.
Metabolism: clinical and experimental 08/2009; 58(10):1503-16. · 2.59 Impact Factor
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ABSTRACT: Recently, several in vitro studies have shown that GPR40 receptor activation by free fatty acids (FFAs) results in glucose-dependent insulin secretion. However, whether GPR40 receptor activation results in glucose-dependent insulin secretion in vivo in rats is not known. Therefore, we evaluated the effect of synthetic GPR40 receptor agonist (compound 1) on glucose tolerance test (GTT) in fed, fasted, and insulin-resistant rats. In oral GTT, intraperitoneal GTT, and intravenous GTT, GPR40 receptor agonist improved glucose tolerance, which was associated with increase in plasma insulin level. Interestingly, in GTTs, the rise in insulin levels in agonist-treated group was directly proportional to the rate of rise and peak levels of glucose in control group. Although glibenclamide, a widely used insulin secretagogue, improved glucose tolerance in all GTTs, it did not display insulin release in intraperitoneal GTT or intravenous GTT. In the absence of glucose load, GPR40 receptor agonist did not significantly change the plasma insulin concentration, but did decrease the plasma glucose concentration. Fasted rats exhibited impaired glucose-stimulated insulin secretion (GSIS) as compared with fed rats. Compound 1 potentiated GSIS in fasted state but failed to do so in fed state. Suspecting differential pharmacokinetics, a detailed pharmacokinetic evaluation was performed, which revealed the low plasma concentration of compound 1 in fed state. Consequently, we examined the absorption profile of compound 1 at higher doses in fed state; and at a dose at which its absorption was comparable with that in fasted state, we observed significant potentiation of GSIS. Chronic high-fructose (60%) diet feeding resulted in impaired glucose tolerance, which was improved by GPR40 receptor agonist. Therefore, our results demonstrate for the first time that acute GPR40 receptor activation leads to potentiation of GSIS in vivo and improves glucose tolerance even in insulin-resistant condition in rats. Taken together, these results suggest that GPR40 receptor agonists could be potential therapeutic alternatives to sulfonylureas.
Metabolism: clinical and experimental 04/2009; 58(3):333-43. · 2.59 Impact Factor
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Adelheid Kratzer,
Marlene Buchebner,
Thomas Pfeifer,
Tatjana M Becker,
Georg Uray,
Makoto Miyazaki,
Shinobu Miyazaki-Anzai,
Birgit Ebner, Prakash G Chandak,
Rajendra S Kadam, [......],
Helmut Ahammer,
Branislav Radovic,
Michael Trauner,
Gerald Hoefler,
Uday B Kompella,
Guenter Fauler,
Moshe Levi,
Sanja Levak-Frank,
Gerhard M Kostner,
Dagmar Kratky
[show abstract]
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ABSTRACT: Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7alpha-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists.
The Journal of Lipid Research 10/2008; 50(2):312-26. · 5.56 Impact Factor
