| Autor: |
Iqra Hussain, Harini K. Sureshkumar, Michael Bauer, Ignacio Rubio |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cells, Vol 12, Iss 12, p 1668 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2073-4409 |
| DOI: |
10.3390/cells12121668 |
| Popis: |
Background and aims: Sepsis-related liver failure is associated with a particularly unfavorable clinical outcome. Calorie restriction is a well-established factor that can increase tissue resilience, protect against liver failure and improve outcome in preclinical models of bacterial sepsis. However, the underlying molecular basis is difficult to investigate in animal studies and remains largely unknown. Methods: We have used an immortalized hepatocyte line as a model of the liver parenchyma to uncover the role of caloric restriction in the resilience of hepatocytes to inflammatory cell damage. In addition, we applied genetic and pharmacological approaches to investigate the contribution of the three major intracellular nutrient/energy sensor systems, AMPK, mTORC1 and mTORC2, in this context. Results: We demonstrate that starvation reliably protects hepatocytes from cellular damage caused by pro-inflammatory cytokines. While the major nutrient- and energy-related signaling pathways AMPK, mTORC2/Akt and mTORC1 responded to caloric restriction as expected, mTORC1 was paradoxically activated by inflammatory stress in starved, energy-deprived hepatocytes. Pharmacological inhibition of mTORC1 or genetic silencing of the mTORC1 scaffold Raptor, but not its mTORC2 counterpart Rictor, abrogated the protective effect of starvation and exacerbated inflammation-induced cell death. Remarkably, mTORC1 activation in starved hepatocytes was uncoupled from the regulation of autophagy, but crucial for sustained protein synthesis in starved resistant cells. Conclusions: AMPK engagement and paradoxical mTORC1 activation and signaling mediate protection against pro-inflammatory stress exerted by caloric restriction in hepatocytes. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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