ORCID Profile
0000-0003-1541-3695
Current Organisation
UNSW Sydney
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Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.TEM.2022.04.008
Abstract: Atherosclerosis predisposes to myriad cardiovascular complications, including myocardial infarction and stroke. Statins have revolutionised cholesterol management but they do not work for all patients, particularly those with familial hypercholesterolaemia (FH). Genome-wide association studies have linked SNPs at orphan G protein-coupled receptor 146 (GPR146) to human atherosclerosis but how GPR146 influences serum cholesterol homeostasis was only recently described. Gpr146 deletion in mice reduces serum cholesterol and atherosclerotic plaque burden, confirming GPR146 as a potential therapeutic target for managing circulating cholesterol. Critically, this effect was independent of the low-density lipoprotein receptor. While still an orphan, the activation of GPR146 by serum suggests identification of its endogenous ligand is tantalisingly close. Herein, we discuss the evidence for GPR146 inhibition as a treatment for atherosclerosis.
Publisher: MDPI AG
Date: 08-06-2019
DOI: 10.3390/JCM8060822
Abstract: The zinc finger transcription factor Snail is a known effector of epithelial-to-mesenchymal transition (EMT), a process that underlies the enhanced invasiveness and chemoresistance of common to cancerous cells. Induction of Snail-driven EMT has also been shown to drive a range of pro-survival metabolic adaptations in different cancers. In the present study, we sought to determine the specific role that Snail has in driving EMT and adaptive metabolic programming in pancreatic ductal adenocarcinoma (PDAC) by overexpressing Snail in a PDAC cell line, Panc1, and in immortalized, non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Snail overexpression was able to induce EMT in both pancreatic cell lines through suppression of epithelial markers and upregulation of mesenchymal markers alongside changes in cell morphology and enhanced migratory capacity. Snail-overexpressed pancreatic cells additionally displayed increased glucose uptake and lactate production with concomitant reduction in oxidative metabolism measurements. Snail overexpression reduced maximal respiration in both Panc1 and HPDE cells, with further reductions seen in ATP production, spare respiratory capacity and non-mitochondrial respiration in Snail overexpressing Panc1 cells. Accordingly, lower expression of mitochondrial electron transport chain proteins was observed with Snail overexpression, particularly within Panc1 cells. Modelling of 13C metabolite flux within both cell lines revealed decreased carbon flux from glucose in the TCA cycle in snai1-overexpressing Panc1 cells only. This work further highlights the role that Snail plays in EMT and demonstrates its specific effects on metabolic reprogramming of glucose metabolism in PDAC.
Publisher: Cold Spring Harbor Laboratory
Date: 11-09-2020
DOI: 10.1101/2020.09.11.290486
Abstract: Orphan G protein-coupled receptors (GPCRs) are largely intractable therapeutic targets, owing to the lack of chemical tools for exploring their pharmacology. The discovery of such tools, however, is h ered by a number of unknowns, such as effector coupling and appropriate positive controls. In our 2017 Nature Chemical Biology paper 1 , we developed a computational chemical tool discovery approach called GPCR Contact-Informed Neighboring Pocket (GPCR-CoINPocket). This method predicted pharmacological similarity of GPCRs in a ligand- and structure-independent manner, to enable the discovery of off-target activities of known compounds at orphan GPCRs and hence the identification of so-called surrogate ligands. Our orphan GPCR target for prospective surrogate ligand discovery efforts was GPR37L1, a brain-specific receptor linked to cerebellar development 2 and seizures 3 . We had previously demonstrated that GPR37L1 constitutively coupled to Gαs and generated ligand-independent increases in intracellular cAMP 4§ . Thus, the inverse agonist activities of computationally predicted surrogates were tested in the cAMP response element luciferase (CRE-luc) reporter gene assay in human embryonic kidney (HEK293) cells expressing either vector control or what we thought was untagged GPR37L1 in pcDNA3.1. However, we recently discovered that the GPR37L1 construct used in that study was incorrect: instead of pcDNA3.1, it carried the receptor inserted backwards into a yeast p426GPD vector (hereafter referred to as p426-r37L1). Here, we correct the cloning error and describe our subsequent unsuccessful efforts to re-test the computationally predicted GPR37L1 ligands (triggering an author-initiated retraction of 1 ). We, the authors, are working with the Nature Chemical Biology Editors to retract our 2017 paper ‘Orphan receptor ligand discovery by pickpocketing pharmacological neighbors’ 1 . The present manuscript is under review at Nature Chemical Biology as a Matters Arising accompaniment to the anticipated author-initiated retraction. We initiated the steps towards the retraction upon discovering a regrettable cloning error that put into question the in vitro findings reported in 1 . This action was unanimously agreed upon by all authors. The computational aspects of the original manuscript 1 are unaffected by this error.
Publisher: MDPI AG
Date: 06-2022
Abstract: Understanding the neurogenic causes of obesity may reveal novel drug targets to counter the obesity crisis and associated sequelae. Here, we investigate whether the deletion of GPR37L1, an astrocyte-specific orphan G protein-coupled receptor, affects whole-body energy homeostasis in mice. We subjected male Gpr37l1−/− mice and littermate wildtype (Gpr37l1+/+, C57BL/6J background) controls to either 12 weeks of high-fat diet (HFD) or chow feeding, or to 1 year of chow diet, with body composition quantified by EchoMRI, glucose handling by glucose tolerance test and metabolic rate by indirect calorimetry. Following an HFD, Gpr37l1−/− mice had similar glucose handling, body weight and fat mass compared with wildtype controls. Interestingly, we observed a significantly elevated respiratory exchange ratio in HFD- and chow-fed Gpr37l1−/− mice during daylight hours. After 1 year of chow feeding, we again saw no differences in glucose and insulin tolerance or body weight between genotypes, nor in energy expenditure or respiratory exchange ratio. However, there was significantly lower fat mass accumulation, and higher ambulatory activity in the Gpr37l1−/− mice during night hours. Overall, these results indicate that while GPR37L1 may play a minor role in whole-body metabolism, it is not a viable clinical target for the treatment of obesity.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
No related grants have been discovered for Brendan Wilkins.