Bio

Professional Education


  • Doctor of Philosophy, Universitat Graz (2011)

Stanford Advisors


Publications

Journal Articles


  • miR-206 controls LXR alpha expression and promotes LXR-mediated cholesterol efflux in macrophages BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS Vinod, M., Chennamsetty, I., Colin, S., Belloy, L., De Paoli, F., Schaider, H., Graier, W. F., Frank, S., Kratky, D., Staels, B., Chinetti-Gbaguidi, G., Kostner, G. M. 2014; 1841 (6): 827-835

    Abstract

    Liver X receptors (LXRα and LXRβ) are key transcription factors in cholesterol metabolism that regulate cholesterol biosynthesis/efflux and bile acid metabolism/excretion in the liver and numerous organs. In macrophages, LXR signaling modulates cholesterol handling and the inflammatory response, pathways involved in atherosclerosis. Since regulatory pathways of LXR transcription control are well understood, in the present study we aimed at identifying post-transcriptional regulators of LXR activity. MicroRNAs (miRs) are such post-transcriptional regulators of genes that in the canonical pathway mediate mRNA inactivation. In silico analysis identified miR-206 as a putative regulator of LXRα but not LXRβ. Indeed, as recently shown, we found that miR-206 represses LXRα activity and expression of LXRα and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRα differently in macrophages. Stably overexpressing miR-206 in THP-1 human macrophages revealed an up-regulation and miR-206 knockdown led to a down-regulation of LXRα and its target genes. In support of these results, bone marrow-derived macrophages (BMDMs) from miR-206 KO mice also exhibited lower expression of LXRα target genes. The physiological relevance of these findings was proven by gain- and loss-of-function of miR-206; overexpression of miR-206 enhanced cholesterol efflux in human macrophages and knocking out miR-206 decreased cholesterol efflux from MPMs. Moreover, we show that miR-206 expression in macrophages is repressed by LXRα activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRα that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity.

    View details for DOI 10.1016/j.bbalip.2014.02.006

    View details for Web of Science ID 000335618300001

    View details for PubMedID 24603323

  • Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice JOURNAL OF LIPID RESEARCH Chennamsetty, I., Kostner, K. M., Claudel, T., Vinod, M., Frank, S., Weiss, T. S., Trauner, M., Kostner, G. M. 2012; 53 (11): 2405-2412

    Abstract

    Elevated plasma lipoprotein(a) (LPA) levels are recognized as an independent risk factor for cardiovascular diseases. Our knowledge on LPA metabolism is incomplete, which makes it difficult to develop LPA-lowering medications. Nicotinic acid (NA) is the main drug recommended for the treatment of patients with increased plasma LPA concentrations. The mechanism of NA in lowering LPA is virtually unknown. To study this mechanism, we treated transgenic (tg) APOA mice with NA and measured plasma APOA and hepatic mRNA levels. In addition, mouse and human primary hepatocytes were incubated with NA, and the expression of APOA was followed. Feeding 1% NA reduced plasma APOA and hepatic expression of APOA in tg-APOA mice. Experiments with cultured human and mouse primary hepatocytes in addition to reporter assays performed in HepG2 cells revealed that NA suppresses APOA transcription. The region between -1446 and -857 of the human APOA promoter harboring several cAMP response element binding sites conferred the negative effect of NA. In accordance, cAMP stimulated APOA transcription, and NA reduced hepatic cAMP levels. It is suggested that cAMP signaling might be involved in reducing APOA transcription, which leads to the lowering of plasma LPA.

    View details for DOI 10.1194/jlr.M029769

    View details for Web of Science ID 000309672100015

    View details for PubMedID 22930813

  • FGF19 Signaling Cascade Suppresses APOA Gene Expression ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Chennamsetty, I., Claudel, T., Kostner, K. M., Trauner, M., Kostner, G. M. 2012; 32 (5): 1220-?

    Abstract

    Lipoprotein(a) is a highly atherogenic lipoprotein, whose metabolism is poorly understood. Currently no safe drugs exists that lower elevated plasma lipoprotein(a) concentrations. We therefore focused on molecular mechanisms that influence apolipoprotein(a) (APOA) biosynthesis.Transgenic human APOA mice (tg-APO mice) were injected with 1 mg/kg of recombinant human fibroblast growth factor 19 (FGF19). This led to a significant reduction of plasma APOA and hepatic expression of APOA. Incubation of primary hepatocytes of tg-APOA mice with FGF19 induced ERK1/2 phosphorylation and, in turn, downregulated APOA expression. Repression of APOA by FGF19 was abrogated by specific ERK1/2 phosphorylation inhibitors. The FGF19 effect on APOA was attenuated by transfection of primary hepatocytes with siRNA against the FGF19 receptor 4 (FGFR4). Using promoter reporter assays, mutation analysis, gel shift, and chromatin immune-precipitation assays, an Ets-1 binding element was identified at -1630/-1615bp region in the human APOA promoter. This element functions as an Elk-1 binding site that mediates repression of APOA transcription by FGF19.These findings provide mechanistic insights into the transcriptional regulation of human APOA by FGF19. Further studies in the human system are required to substantiate our findings and to design therapeutics for hyper lipoprotein(a).

    View details for DOI 10.1161/ATVBAHA.111.243055

    View details for Web of Science ID 000303195100027

    View details for PubMedID 22267484

  • Farnesoid X receptor represses hepatic human APOA gene expression JOURNAL OF CLINICAL INVESTIGATION Chennamsetty, I., Claudel, T., Kostner, K. M., Baghdasaryan, A., Kratky, D., Levak-Frank, S., Frank, S., Gonzalez, F. J., Trauner, M., Kostner, G. M. 2011; 121 (9): 3724-3734

    Abstract

    High plasma concentrations of lipoprotein(a) [Lp(a), which is encoded by the APOA gene] increase an individual's risk of developing diseases, such as coronary artery diseases, restenosis, and stroke. Unfortunately, increased Lp(a) levels are minimally influenced by dietary changes or drug treatment. Further, the development of Lp(a)-specific medications has been hampered by limited knowledge of Lp(a) metabolism. In this study, we identified patients suffering from biliary obstructions with very low plasma Lp(a) concentrations that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human APOA (tg-APOA mice) lowered plasma concentrations and hepatic expression of APOA. To test whether farnesoid X receptor (FXR), which is activated by bile acids, was responsible for the low plasma Lp(a) levels in cholestatic patients and mice, we treated tg-APOA and tg-APOA/Fxr-/- mice with cholic acid. FXR activation markedly reduced plasma concentrations and hepatic expression of human APOA in tg-APOA mice but not in tg-APOA/Fxr-/- mice. Incubation of primary hepatocytes from tg-APOA mice with bile acids dose dependently downregulated APOA expression. Further analysis determined that the direct repeat 1 element between nucleotides -826 and -814 of the APOA promoter functioned as a negative FXR response element. This motif is also bound by hepatocyte nuclear factor 4α (HNF4α), which promotes APOA transcription, and FXR was shown to compete with HNF4α for binding to this motif. These findings may have important implications in the development of Lp(a)-lowering medications.

    View details for DOI 10.1172/JCI45277

    View details for Web of Science ID 000294753700037

    View details for PubMedID 21804189

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