mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species

Hosios, Aaron M.; Wilkinson, Meghan; McNamara, Molly C.; Kalafut, Krystle; Torrence, Margaret E.; Asara, John M.; Manning, Brendan D.

doi:10.1038/s42255-022-00706-6

Cited by 21 publications

(15 citation statements)

References 63 publications

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“…DGAT1 converts these fatty acids into triacylglycerol, which promotes lipid droplet biogenesis and prevents lipotoxic damage to mitochondria 126 , 127 . In a study published in 2022, mTORC1 inhibition or nutrient deprivation were demonstrated to increase the delivery of endosomal cargo to lysosomes and promote triacylglycerol accumulation through lysosome-dependent but autophagy-independent hydrolysis of phospholipids 128 . Increased phospholipase expression and activity might also account for the hydrolysis of phospholipids under these conditions 128 .…”

Section: Lipid Droplet Biogenesis As a Response To Cellular Stressmentioning

confidence: 99%

“…In a study published in 2022, mTORC1 inhibition or nutrient deprivation were demonstrated to increase the delivery of endosomal cargo to lysosomes and promote triacylglycerol accumulation through lysosome-dependent but autophagy-independent hydrolysis of phospholipids 128 . Increased phospholipase expression and activity might also account for the hydrolysis of phospholipids under these conditions 128 . Mechanistic differences aside, cells seem to adapt to starvation by increasing membrane turnover and the flux of fatty acids and other lipid intermediates to the ER for triacylglycerol synthesis and lipid droplet biogenesis.…”

Section: Lipid Droplet Biogenesis As a Response To Cellular Stressmentioning

confidence: 99%

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Lipid droplet biogenesis and functions in health and disease

2023

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Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. Here, we provide an update on the current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a key role for lipid droplet biogenesis in alleviating cellular stresses. We also discuss therapeutic strategies of targeting lipid droplet biogenesis, growth or degradation that could be applied in the future to common diseases, such as cancer, hepatic steatosis and viral infection.

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Section: Lipid Droplet Biogenesis As a Response To Cellular Stressmentioning

confidence: 99%

Section: Lipid Droplet Biogenesis As a Response To Cellular Stressmentioning

confidence: 99%

Lipid droplet biogenesis and functions in health and disease

2023

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“…While we believe that this study is the first to identify a relationship of synthetic lethality between PIKfyve and fatty acid synthesis in PDAC, PIKfyve was recently shown to play a role in lipid metabolism through its role in lysosome function 67 . In this study, the authors inhibited de novo fatty acid synthesis and found that cells undergo increased phospholipid turnover in a lysosome- and PIKfyve-dependent process.…”

Section: Discussionmentioning

confidence: 83%

Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer

Cheng,

Hu,

Mannan

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism12. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered thatPIKFYVEis overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulatede novolipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency onde novolipid metabolism pathways, by upregulating genes such asFASNandACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver ofde novolipid synthesis, specifically enhancingFASNandACACAlevels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.

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“…Therefore, it was paradoxical that both genetic and pharmacological inhibition of mTORC1 led to an increased lipid burden in our microglia. Interestingly, a recent study investigating mTORC1-controlled lipid accumulation in several cell lines found that de novo lipid synthesis upon mTOR activation mainly produced phospholipids for membrane growth, while mTOR inhibition led to a reversal and lysosome-dependent breakdown of phospholipids into triglycerides that are deposited in lipid droplets for energy storage 37 . Therefore, the lipids accumulating in mTORC1-suppressed microglia would be expected to primarily be triglyceride species, and fewer cholesteryl esters, as was found in hepatocytes of a Rheb-/- mouse model 38 .…”

Section: Discussionmentioning

confidence: 99%

An arrayed CRISPR/Cas9 screen identifies mTORC1 as a regulator of lipid droplet accumulation in APOE E3 and APOE KO iPSC-derived microglia

Meier,

Larsen,

Wanke

et al. 2024

Preprint

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Variants of the Apolipoprotein E (APOE) gene, particularly the E4 allele, are significantly associated with an increased risk of Alzheimer's Disease and have been implicated in neuroinflammatory processes due to disrupted lipid metabolism. Lipid alterations can manifest in glial cells as an excessive buildup of lipids, potentially contributing to neuroinflammation. In this study, we observed a heightened lipid load in APOE-deficient human induced pluripotent stem cell (iPSC)-derived microglia relative to cells with other APOE isoforms. To explore the mechanisms governing lipid handling within microglia, we established a technique for the nucleofection of CRISPR/Cas9 ribonucleoprotein complexes into iPSC-derived myeloid cells. Utilizing this method, we performed a targeted screen to identify key upstream modifiers in lipid droplet formation. Our findings highlight the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as a pivotal influence on lipid storage in microglia with both APOE3 and APOE knockout genotypes, underscoring its role in lipid dysregulation associated with Alzheimer's Disease and neuroinflammation.

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mTORC1 regulates a lysosome-dependent adaptive shift in intracellular lipid species

Cited by 21 publications

References 63 publications

Lipid droplet biogenesis and functions in health and disease

Lipid droplet biogenesis and functions in health and disease

Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer

An arrayed CRISPR/Cas9 screen identifies mTORC1 as a regulator of lipid droplet accumulation in APOE E3 and APOE KO iPSC-derived microglia

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