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Christiane Rennert

About Christiane Rennert:
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SEEK ID: https://seek.lisym.org/people/12

Location:  Germany

Expertise: Not specified

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ORCID: https://orcid.org/0000-0001-8753-8441

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The Hedgehog Signalling Pathway (LiSyM-JGMMS)

Dr. Madlen Matz-Soja (University of Leipzig) investigates the importance of a control mechanism - the hedgehog signaling pathway - for fatty liver disease. She has shown that the signaling pathway directs how liver cells in NAFLD accumulate fat. Hedgehog also affects sex hormones in the liver. Therefore, Matz-Soya hopes to clarify why women and men suffer from cirrhosis and liver cancer with varying degrees of frequency.

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/our-work/junior-group/hedgehog-influences

Start date: 1st Jan 2016

LiSyM network

This comprises the whole LiSyM network

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org

Start date: 1st Jan 2016

SAC mice RNA microarray
The Hedgehog Signalling Pathway (LiSyM-JGMMS)

RNA microarray made with primary hepatocytes from female mice with hepatocyte-specific, embryonic knockout of Smoothened

Creator: Christiane Rennert

Submitter: Christiane Rennert

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Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver
The Hedgehog Signalling Pathway (LiSyM-JGMMS)

Abstract (Expand)

In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog … (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

Authors: Luise Spormann, Christiane Rennert, Erik Kolbe, Fritzi Ott, Carolin Lossius, Robert Lehmann, Rolf Gebhardt, Thomas Berg, Madlen Matz-Soja

Date Published: 1st Aug 2020

Publication Type: Journal

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human
LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

Abstract (Expand)

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and … control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Authors: Erik Kolbe, Susanne Aleithe, Christiane Rennert, Luise Spormann, Fritzi Ott, David Meierhofer, Robert Gajowski, Claus Stöpel, Stefan Hoehme, Michael Kücken, Lutz Brusch, Michael Seifert, Witigo von Schoenfels, Clemens Schafmayer, Mario Brosch, Ute Hofmann, Georg Damm, Daniel Seehofer, Jochen Hampe, Rolf Gebhardt, Madlen Matz-Soja

Date Published: 1st Dec 2019

Publication Type: Not specified

Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis.
The Hedgehog Signalling Pathway (LiSyM-JGMMS)

Abstract (Expand)

BACKGROUND & AIMS: The mammalian circadian clock controls various aspects of liver metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling as a novel regulator … of liver lipid metabolism. Herein, we investigated crosstalk between hepatic Hh signaling and circadian rhythm. METHODS: Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were used for analysis of metabolic alterations and behavior. RESULTS: Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro. Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1 in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely, SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent alterations in various genes, particularly those associated with lipid metabolism. The clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the liver to a high-fat diet or to differently timed starvation. CONCLUSIONS: For the first time, Hh signaling in hepatocytes was found to be time-of-day dependent and to feed back on the circadian clock. Our findings suggest an integrative role of Hh signaling, mediated mainly by GLI factors, in maintaining homeostasis of hepatic lipid metabolism by balancing the circadian clock. LAY SUMMARY: The results of our investigation show for the first time that the Hh signaling in hepatocytes is time-of-day dependent, leading to differences not only in transcript levels but also in the amount of Hh ligands in peripheral blood. Conversely, Hh signaling is able to feed back to the circadian clock.

Authors: E. Marbach-Breitruck, M. Matz-Soja, U. Abraham, W. Schmidt-Heck, S. Sales, C. Rennert, M. Kern, S. Aleithe, L. Spormann, C. Thiel, R. Gerlini, K. Arnold, N. Kloting, R. Guthke, D. Rozman, R. Teperino, A. Shevchenko, A. Kramer, R. Gebhardt

Date Published: 4th Feb 2019

Publication Type: Not specified

The Diurnal Timing of Starvation Differently Impacts Murine Hepatic Gene Expression and Lipid Metabolism – A Systems Biology Analysis Using Self-Organizing Maps
The Hedgehog Signalling Pathway (LiSyM-JGMMS)

Abstract

Not specified

Authors: Christiane Rennert, Sebastian Vlaic, Eugenia Marbach-Breitrück, Carlo Thiel, Susanne Sales, Andrej Shevchenko, Rolf Gebhardt, Madlen Matz-Soja

Date Published: 10th Sep 2018

Publication Type: Not specified

Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility
The Hedgehog Signalling Pathway (LiSyM-JGMMS), LiSyM network

Abstract (Expand)

The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer … therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.

Authors: Christiane Rennert, Franziska Eplinius, Ute Hofmann, Janina Johänning, Franziska Rolfs, Wolfgang Schmidt-Heck, Reinhardt Guthke, Rolf Gebhardt, Albert M. Ricken, Madlen Matz-Soja

Date Published: 30th May 2017

Publication Type: Not specified

Connection of Hedgehog signaling and hepatic steroidogenesis, androgenization and infertility
The Hedgehog Signalling Pathway (LiSyM-JGMMS)

Poster for 1st annual LiSyM Meeting

Creator: Christiane Rennert

Submitter: Christiane Rennert

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