ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration

Muliyil, Sonia; Levet, Clémence; Düsterhöft, Stefan; Dulloo, Iqbal; Cowley, Sally A.; Freeman, Matthew

doi:10.1101/2020.01.09.900209

Cited by 7 publications

(9 citation statements)

References 77 publications

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“…Similar reasoning suggests a reinterpretation of two previous studies in the adult Drosophila retina, which reported that glial lipid droplets induced either by mitochondrial defects or by loss of ADAM17 metalloprotease act to promote neurodegeneration [57,58]. This conclusion was based on evidence that decreasing lipid droplets via the overexpression of Bmm/ATGL leads to less neurodegeneration.…”

Section: A General Strategy For Distinguishing Between Different Lipisupporting

confidence: 70%

Adipose Triglyceride Lipase protects the endocytosis of renal cells on a high fat diet inDrosophila

Lubojemska

Stefana

Lampe

et al. 2020

Preprint

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Obesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet rodent models but their precise role remains unclear. Here, we establish a high-fat diet model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell-type specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A high-fat diet drives nephrocyte lipid uptake via the multiligand receptor Cubilin, leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with ER and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL) and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue high-fat diet induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a high-fat diet via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.

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Section: A General Strategy For Distinguishing Between Different Lipisupporting

confidence: 70%

Adipose Triglyceride Lipase protects the endocytosis of renal cells on a high fat diet inDrosophila

Lubojemska

Stefana

Lampe

et al. 2020

Preprint

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“…ADAM17 is increased in aging in mice and contributes to vascular remodeling and impaired endothelial wall shear stress mechanosensing [ 100 ]. Interestingly, in Drosophila , ADAM17 showed a protective role in neuronal and glial degeneration in the aging retina [ 101 ].…”

Section: The Role Of Aging On Bbb Function and Expression Of Sars-cov...mentioning

confidence: 99%

Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19

Adesse

Gladulich

Alvarez-Rosa

et al. 2022

Fluids Barriers CNS

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COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. The blood–brain barrier (BBB) was suggested to be the major route of SARS-CoV-2 infection of the brain. Functionally, the BBB is created by an interactome between endothelial cells, pericytes, astrocytes, microglia, and neurons, which form the neurovascular units (NVU). However, at present, the interactions of SARS-CoV-2 with the NVU and the outcomes of this process are largely unknown. Moreover, age was described as one of the most prominent risk factors for hospitalization and deaths, along with other comorbidities such as diabetes and co-infections. This review will discuss the impact of SARS-CoV-2 on the NVU, the expression profile of SARS-CoV-2 receptors in the different cell types of the CNS and the possible role of aging in the neurological outcomes of COVID-19. A special emphasis will be placed on mitochondrial functions because dysfunctional mitochondria are also a strong inducer of inflammatory reactions and the “cytokine storm” associated with SARS-CoV-2 infection. Finally, we will discuss possible drug therapies to treat neural endothelial function in aged patients, and, thus, alleviate the neurological symptoms associated with COVID-19.

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“…Dysregulated expression of ADAMs was reported in the RPE-choroid complex of AMD patients (16). In addition, the latest study showed that loss of ADAM17, one of intensively studied ADAM members, promotes AMD-like phenotypes (17).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

“…Although genetic and environmental factors have been associated with the development of AMD, the etiology and pathogenesis of AMD remain largely unknown. Recently, dysfunctional MMPs have been reported to be associated with AMD in human beings ( 15 , 16 , 17 ). Genome-wide association studies showed that variations on tissue inhibitor of metalloproteinase 3 (TIMP3) are associated with the onset of AMD ( 15 ).…”

mentioning

confidence: 99%

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ADAM17 mediates ectodomain shedding of the soluble VLDL receptor fragment in the retinal epithelium

Takahashi

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration

Cited by 7 publications

References 77 publications

Adipose Triglyceride Lipase protects the endocytosis of renal cells on a high fat diet inDrosophila

Adipose Triglyceride Lipase protects the endocytosis of renal cells on a high fat diet inDrosophila

Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19

ADAM17 mediates ectodomain shedding of the soluble VLDL receptor fragment in the retinal epithelium

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