Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation

Alasdair Leeson-Payne; Jean Iyinikkel; Cameron Malcolm; Brian Y H Lam; Nadine Sommer; Georgina K C Dowsett; Pablo Blanco Martinez de Morentin; Dawn Thompson; Alasdair MacKenzie; Raffaella Chianese; Katherine A Kentistou; Eugene J.  Gardner; John R.B. Perry; Felix Grassmann; John Speakman; Justin Rochford; Giles S. H. Yeo; Fiona Murray; Lora Heisler

doi:10.1016/j.cmet.2024.03.016

Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation

Alasdair Leeson-Payne
, Jean Iyinikkel
, Cameron Malcolm
, Brian Y H Lam
, Nadine Sommer
, Georgina K C Dowsett
, Pablo Blanco Martinez de Morentin
, Dawn Thompson
, Alasdair MacKenzie
, Raffaella Chianese
, Katherine A Kentistou
, Eugene J. Gardner
, John R.B. Perry
, Felix Grassmann
, John Speakman
, Justin Rochford
, Giles S. H. Yeo
, Fiona Murray
, Lora Heisler^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

13 Downloads (Pure)

Abstract

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD), however there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G-protein coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in brain. Next, we generated the first single cell level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite regulating hypothalamic neurons. CRISPR/Cas9-deleted Gpr75 mice fed a palatable Western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here we provide a significant advance in understanding of the expression and function of GPR75, demonstrating it is a promising pharmaceutical target for NAFLD treatment.

Original language	English
Pages (from-to)	1076-1087
Number of pages	12
Journal	Cell Metabolism
Volume	36
Issue number	5
Early online date	22 Apr 2024
DOIs	https://doi.org/10.1016/j.cmet.2024.03.016
Publication status	Published - 7 May 2024

Bibliographical note

Open Access via the Elsevier Agreement

L.K.H. designed the experiments with input from F.M., G.S.H.Y., and J.J.R.; F.M. and J.I. created the CRISPR-Cas9-deleted Gpr75 mouse line with input from A.M.; A.L.-P., C.M., B.Y.H.L., G.K.C.D., N.S., P.B.M.d.M., R.C., K.K., E.J.G., J.R.B.P., F.G., J.R.S., and J.J.R. performed experiments and/or data analysis; D.T. provided reagents and intellectual contributions; and L.K.H. and A.L.-P. wrote the manuscript with input from all other authors.

Data Availability Statement

Materials availability

Mouse lines generated in this study are available at request to co-corresponding author, Fiona Murray ([email protected]

).
Data and code availability

Single-cell RNA-seq data have been deposited at Cambridge Repository and are publicly available. The hypothalamic nucSeq are available in an interactive CellxGene viewer (available via https://www.mrl.ims.cam.ac.uk
). Additionally, the Seurat object containing the HypoMap is deposited at University of Cambridge’s Apollo Repository (https://doi.org/10.17863/CAM.87955) in standard RDS format. The source data for the HypoMap can be found CELLxGENE (https://cellxgene.cziscience.com/collections/d86517f0-fa7e-4266-b82e-a521350d6d36) accession numbers: GSE132355, GSE193921, GSE132730, GSE207736, GSE113576, GSE172204, SRP135960, GSE167927, GSE172461, GSE130597, GSE132608, GSE119960, GSE93374, GSE125065, GSE117295, GSE146692, GSE87544. All code is publicly available as of the date of publication and DOIs are listed in the key resources table. Details of any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. Source data are provided with this paper and all data will be shared by the lead contact upon request.

Funding

The authors thank Thomas McSkimming, Samuel Bundy, Samriti Juneja, Susan Berry, Tongshuo Hu, Yinan Zhang, and staff within the University of Aberdeen Medical Research Facility and the Microscopy Facility staff for their technical assistance. This research has been conducted using data from UKBB (project number 32974), a major biomedical database. Work was supported by the Biotechnology and Biological Sciences Research Council (BB/R01857X/1 and BB/V016849/1 to L.K.H.; BBSRC Mitigation Fund BB/W510634/1 to A.L.-P., L.K.H., and F.M.; BB/V015869/1 to J.J.R.; and BB/S017593/1 to B.Y.H.L.), the Medical Research Council (MC/PC/15077 to L.K.H. and MC_UU_00014/1 to G.S.H.Y.), Wellcome Trust Seed Award (205862/Z/16/Z to F.M.), TENOVUS (G20.09 to F.M. and D.T.), and Wellcome Trust Institutional Strategic Support Fund to the University of Aberdeen (to L.K.H., F.M., and A.L.-P.). C.M. is funded by a BBSRC (Eastbio) CASE 4-year PhD studentship. N.S. is supported by a BBSRC Eastbio PhD studentship. Next-generation sequencing was performed by the IMS Genomics and transcriptomics core facility, which is supported by the MRC (MC_UU_00014/5), the Wellcome Trust (208363/Z/17/Z), and the Cancer Research UK Cambridge Institute Genomics Core. G.K.C.D. is funded by a BBSRC CASE 4-year PhD studentship, co-funded by Novo Nordisk.

Funders	Funder number
Biotechnology and Biological Sciences Research Council	BB/R01857X/1, BB/V016849/1, BB/W510634/1, BB/V015869/1 , BB/S017593/1
Medical Research Council	MC/PC/15077, MC_UU_00014/1, MC_UU_00014/5
Wellcome Trust	205862/Z/16/Z, 208363/Z/17/Z

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

G protein-coupled receptor
Gpr75
NAFLD
obesity
physical activity
fatty liver

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Cite this

Leeson-Payne, A., Iyinikkel, J., Malcolm, C., Lam, B. Y. H., Sommer, N., Dowsett, G. K. C., Blanco Martinez de Morentin, P., Thompson, D., MacKenzie, A., Chianese, R., Kentistou, K. A., Gardner, E. J., Perry, J. R. B., Grassmann, F., Speakman, J., Rochford, J., Yeo, G. S. H., Murray, F., & Heisler, L. (2024). Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation. Cell Metabolism, 36(5), 1076-1087. https://doi.org/10.1016/j.cmet.2024.03.016

Leeson-Payne, A, Iyinikkel, J, Malcolm, C, Lam, BYH, Sommer, N, Dowsett, GKC, Blanco Martinez de Morentin, P, Thompson, D , MacKenzie, A, Chianese, R, Kentistou, KA, Gardner, EJ, Perry, JRB, Grassmann, F, Speakman, J , Rochford, J, Yeo, GSH, Murray, F & Heisler, L 2024, 'Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation', Cell Metabolism, vol. 36, no. 5, pp. 1076-1087. https://doi.org/10.1016/j.cmet.2024.03.016

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abstract = "Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD), however there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G-protein coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in brain. Next, we generated the first single cell level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite regulating hypothalamic neurons. CRISPR/Cas9-deleted Gpr75 mice fed a palatable Western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here we provide a significant advance in understanding of the expression and function of GPR75, demonstrating it is a promising pharmaceutical target for NAFLD treatment.",

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AU - Sommer, Nadine

AU - Dowsett, Georgina K C

AU - Blanco Martinez de Morentin, Pablo

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AU - MacKenzie, Alasdair

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Loss of GPR75 protects against non-alcoholic fatty liver disease and body fat accumulation

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

Access to Document

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