Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes

Sekar, Revathi; Motzler, Karsten; Kwon, Yongseok; Novikoff, Aaron; Jülg, Julia; Najafi, Bahar; Wang, Surui; Warnke, Anna-Luisa; Seitz, Susanne; Hass, Daniela; Gancheva, Sofiya; Kahl, S.; Yang, Bin; Finan, Brian; Schwarz, Kathrin; Okun, Juergen G.; Roden, Michael; Blüher, Matthias; Müller, Timo; Krahmer, Natalie; Behrends, Christian; Plettenburg, Oliver; Miączyńska, Marta; Herzig, Stephan; Zeigerer, Anja

doi:10.1016/j.cmet.2022.09.022

Cited by 12 publications

(4 citation statements)

References 80 publications

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“…In CES3 knockout mice, insulin sensitivity and glucose tolerance improved (Wei et al 2010 ). In animal models, VPS37A changed intracellular receptor localization such that overexpression of VPS37A resulted in decreased blood glucose levels (Sekar 2022 ) and in Long-COVID may be a protective effect to counteract the AP3S2 and CES3 overexpression. Overexpression of SRC is involved with colon cancer and often results in metastasis via its signalling pathways (Chen et al 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Patel

Knauer

Nicholson

et al. 2023

Mol Med

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Background Survivors of acute COVID-19 often suffer prolonged, diffuse symptoms post-infection, referred to as “Long-COVID”. A lack of Long-COVID biomarkers and pathophysiological mechanisms limits effective diagnosis, treatment and disease surveillance. We performed targeted proteomics and machine learning analyses to identify novel blood biomarkers of Long-COVID. Methods A case–control study comparing the expression of 2925 unique blood proteins in Long-COVID outpatients versus COVID-19 inpatients and healthy control subjects. Targeted proteomics was accomplished with proximity extension assays, and machine learning was used to identify the most important proteins for identifying Long-COVID patients. Organ system and cell type expression patterns were identified with Natural Language Processing (NLP) of the UniProt Knowledgebase. Results Machine learning analysis identified 119 relevant proteins for differentiating Long-COVID outpatients (Bonferonni corrected P < 0.01). Protein combinations were narrowed down to two optimal models, with nine and five proteins each, and with both having excellent sensitivity and specificity for Long-COVID status (AUC = 1.00, F1 = 1.00). NLP expression analysis highlighted the diffuse organ system involvement in Long-COVID, as well as the involved cell types, including leukocytes and platelets, as key components associated with Long-COVID. Conclusions Proteomic analysis of plasma from Long-COVID patients identified 119 highly relevant proteins and two optimal models with nine and five proteins, respectively. The identified proteins reflected widespread organ and cell type expression. Optimal protein models, as well as individual proteins, hold the potential for accurate diagnosis of Long-COVID and targeted therapeutics.

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Section: Discussionmentioning

confidence: 99%

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Patel

Knauer

Nicholson

et al. 2023

Mol Med

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“…Primary murine hepatocytes from 8 to 12-weeks-old C57BL6/N mice (Janvier Labs) were isolated using collagenase perfusion [ 48 , 49 ]. 2 × 10 5 cells per well were seeded in collagen-coated (Sigma–Aldrich) 24-well plates (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…2 × 10 5 cells per well were seeded in collagen-coated (Sigma–Aldrich) 24-well plates (Thermo Fisher Scientific). Hepatocytes were cultured in William's Medium E (PAN-Biotech) containing 10% FCS (PAN-Biotech), 5% Pen/Strep (Thermo Fisher Scientific) and 100 nM dexamethasone (Sigma–Aldrich) and maintained at 37 °C and 5% CO 2 for 1 h. Next, cells were washed with PBS (Thermo Fisher Scientific) and incubated with 80 nM Pklr or control siRNA (SMARTPool, Dharmacon; control siRNA was non-targeting siRNA designed and microarray tested by the supplier for minimal targeting of human, mouse or rat genes) and interferin (1.2 μL/well) (Polyplus) for 6 h until a second layer of collagen was added to maintain the cells in sandwich culture [ 49 ] in William's Medium E medium containing 10% FCS, 5% Pen/Strep. Medium was changed every second day.…”

Section: Methodsmentioning

confidence: 99%

Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis

Nieborak

Lukauskas

Capellades

et al. 2023

Molecular Metabolism

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“…Our recent studies began to unravel particular metabolic pathways regulated by ESCRT. VPS37A, one of ESCRT-I components was shown to have a specific function in the liver in mediating glucagon receptor degradation, thereby regulating hepatic glucose production [34]. In another study we discovered that by fueling lysosomes with macromolecules from multiple sources, ESCRT-I promotes substrate-specific mTORC1 signaling that inhibits TFEB/TFE3 transcription factors.…”

Section: Introductionmentioning

confidence: 99%

NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency

Cendrowski,

Wrobel,

Mazur

et al. 2024

Preprint

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Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, and increased the expression of genes encoding glycolytic enzymes. Although depletion of ESCRT-I components did not impair mitochondrial biogenesis and ATP-linked respiration it caused intracellular accumulation of lipids and increased lactate production, hallmarks of aerobic glycolysis. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways. Moreover, inhibiting lysosomal activity phenocopied the altered expression of metabolic genes and lipid homeostasis observed for ESCRT-I deficiency, indicating that ESCRT-I restricts glycolysis by mediating lysosomal degradation.

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Vps37a regulates hepatic glucose production by controlling glucagon receptor localization to endosomes

Cited by 12 publications

References 80 publications

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Organ and cell-specific biomarkers of Long-COVID identified with targeted proteomics and machine learning

Depletion of pyruvate kinase (PK) activity causes glycolytic intermediate imbalances and reveals a PK-TXNIP regulatory axis

NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency

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