G protein-coupled receptor GPR35 suppresses lipid accumulation in hepatocytes

Lin, L.-C., Quon, T., Engberg, S., Mackenzie, A. E., Tobin, A. B. and Milligan, G. (2021) G protein-coupled receptor GPR35 suppresses lipid accumulation in hepatocytes. ACS Pharmacology and Translational Science, 4(6), pp. 1835-1848. (doi: 10.1021/acsptsci.1c00224) (PMID:34927014)

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Although prevalent, nonalcoholic fatty liver disease is not currently treated effectively with medicines. Initially, using wild-type and genome-edited clones of the human hepatocyte cell line HepG2, we show that activation of the orphan G protein-coupled receptor GPR35 is both able and sufficient to block liver X-receptor-mediated lipid accumulation. Studies on hepatocytes isolated from both wild-type and GPR35 knock-out mice were consistent with a similar effect of GPR35 agonists in these cells, but because of marked differences in the pharmacology of GPR35 agonists and antagonists at the mouse and human orthologues, as well as elevated basal lipid levels in hepatocytes from the GPR35 knock-out mice, no definitive conclusion could be reached. To overcome this, we generated and characterized a transgenic knock-in mouse line in which the corresponding human GPR35 splice variant replaced the mouse orthologue. In hepatocytes from these humanized GPR35 mice, activation of this receptor was shown conclusively to prevent, and also reverse, lipid accumulation induced by liver X-receptor stimulation. These studies highlight the potential to target GPR35 in the context of fatty liver diseases.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Quon, Dr Tezz and Tobin, Andrew and Lin, Dr Li-Chiung and Mackenzie, Miss Amanda and Milligan, Professor Graeme
Authors: Lin, L.-C., Quon, T., Engberg, S., Mackenzie, A. E., Tobin, A. B., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:ACS Pharmacology and Translational Science
Publisher:American Chemical Society
ISSN (Online):2575-9108
Published Online:30 November 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in ACS Pharmacology and Translational Science 4(6): 1835-1848
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173305Defining the functional roles of the enigmatic G protein coupled receptor GPR35Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/P000649/1MCSB - Molecular Pharmacology
173689Defining the functional role of the enigmatic G protein coupled receptor GPR35 - Leicester application - PART BAndrew TobinBiotechnology and Biological Sciences Research Council (BBSRC)BB/P00069X/1MCSB - Administration
302024Flexible Talent Mobility AccountsCarl GoodyearBiotechnology and Biological Sciences Research Council (BBSRC)BB/R506576/1III - Immunology