Sex-specific dimorphism in cellular stress response upon mTOR inhibition revealed by podocyte specific RNA sequencing

Guergen, Dennis; Kusch, Angelika; Stottmeister, Christin; Al-Diab, Ola; Grahammer, Florian; Huber, Tobias B.; Rajewski, Nikolaus; Dragun, Duska

doi:10.1097/01.tp.0000542903.13353.0a

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“…However, the mitochondrial membrane potential was elevated in the hepatocytes from both sexes. In contrast to the sexual dimorphism in vivo, we did not observe differences in vitro, although rapamycin is known to exhibit sex-specific effects in cardiac and renal tissue [51][52][53]. The only sex-specific differences we detected were based on rapamycin effects on transcriptional level.…”

Section: The Sensitivity Of Energy Metabolism To Hepatocyte-specific contrasting

confidence: 93%

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Spormann

Rennert

Kolbe

et al. 2020

Cells

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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.

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Section: The Sensitivity Of Energy Metabolism To Hepatocyte-specific contrasting

confidence: 93%

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Spormann

Rennert

Kolbe

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

Sex-specific dimorphism in cellular stress response upon mTOR inhibition revealed by podocyte specific RNA sequencing

Cited by 1 publication

References 0 publications

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

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