Article ; Online: The Absence of HIF-1α Increases Susceptibility to Leishmania donovani Infection via Activation of BNIP3/mTOR/SREBP-1c Axis
Cell Reports, Vol 30, Iss 12, Pp 4052-4064.e
2020 Volume 7
Abstract: Summary: Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we ... ...
| Abstract | Summary: Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L. donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α−/− macrophages. L. donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells. : Mesquita et al. show that genetic deficiency of HIF-1α in the myeloid compartment promotes de novo lipogenesis through the BNIP3/mTOR/SREBP-1c axis. This is associated with higher susceptibility to Leishmania donovani infection, which is reduced upon pharmacological inhibition of fatty acid synthesis. Keywords: HIF-1α, visceral leishmaniasis, macrophages, lipogenesis, SREBP-1c, FASN, acetate, myeloid cells |
|---|---|
| Keywords | Biology (General) ; QH301-705.5 |
| Language | English |
| Publishing date | 2020-03-01T00:00:00Z |
| Publisher | Elsevier |
| Document type | Article ; Online |
| Database | BASE - Bielefeld Academic Search Engine (life sciences selection) |
Full text online
More links
Kategorien
Inter-library loan at ZB MED
Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.