Dataset Information

A Fbxo48 inhibitor prevents pAMPKa degradation and ameliorates insulin resistance

ABSTRACT: Beas-2b cells treated with vehicle or BC1618 compound, which targets the ubiquitin E3 ligase for targeted degradation of pAMPKa protein. Cell lysate was subjected to mass spectrometry for phosphoproteomics to uncover alterations in the phosphoproteome.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Bill Chen

PROVIDER: MSV000086334 | MassIVE | Tue Oct 20 11:15:00 BST 2020

REPOSITORIES: MassIVE

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Publications

A Fbxo48 inhibitor prevents pAMPKα degradation and ameliorates insulin resistance.

Liu Yuan Y Jurczak Michael J MJ Lear Travis B TB Lin Bo B Larsen Mads B MB Kennerdell Jason R JR Chen Yanwen Y Huckestein Brydie R BR Nguyen Matthew K MK Tuncer Ferhan F Jiang Yu Y Monga Satdarshan P SP O'Donnell Christopher P CP Finkel Toren T Chen Bill B BB Mallampalli Rama K RK

Nature chemical biology 20210125 3

The adenosine monophosphate (AMP)-activated protein kinase (Ampk) is a central regulator of metabolic pathways, and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signal ...[more]

PMID: 33495648

Similar Datasets

Project description:Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesise that its aetiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made M-bM-^@M-^\insulin resistantM-bM-^@M-^] by treatment with tumour necrosis factor (TNF-alpha and then reversed with aspirin and troglitazone (M-bM-^@M-^\re-sensitizedM-bM-^@M-^]). The GES consisted of 5 genes whose expression levels best discriminated between the insulin resistant and insulin re-sensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed using aspirin and troglitazone. This screen identified both known and new insulin sensitising compounds including non-steroidal anti-inflammatory agents, beta-adrenergic antagonists, beta-lactams and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study (n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels, P < 0.001). These findings show that GES technology can be used for both discovery of insulin sensitising compounds and characterisation of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalised medicine approach to type 2 diabetes. Three-condition experiment, Vehicle, TNF and TNF+ASA+TGZ with biological replicates: 22 Vehicle, 21 TNF and 21 TNF+ASA+TGZ , independently grown and harvested. One replicate per array.