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 B Martinez de Morentin; Dawn Thompson; Alasdair Mackenzie; Raffaella Chianese; Katherine Kentistou; Eugene J Gardner; John R B Perry; Felix Grassmann; John R Speakman; Justin J Rochford; Giles S H Yeo; Fiona Murray; Lora K Heisler

doi:10.1016/j.cmet.2024.03.016

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

Cell Metab. 2024 Apr 18:S1550-4131(24)00120-7. doi: 10.1016/j.cmet.2024.03.016. Online ahead of print.

Authors

Alasdair Leeson-Payne¹, Jean Iyinikkel², Cameron Malcolm², Brian Y H Lam³, Nadine Sommer¹, Georgina K C Dowsett³, Pablo B Martinez de Morentin¹, Dawn Thompson², Alasdair Mackenzie², Raffaella Chianese¹, Katherine Kentistou⁴, Eugene J Gardner⁴, John R B Perry⁵, Felix Grassmann⁶, John R Speakman⁷, Justin J Rochford¹, Giles S H Yeo³, Fiona Murray⁸, Lora K Heisler⁹

Affiliations

¹ The Rowett Institute, University of Aberdeen, Aberdeen, UK.
² Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
³ Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK.
⁴ Medical Research Council Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
⁵ Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Medical Research Council Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
⁶ Institute for Clinical Research and Systems Medicine, Health and Medical University, Potsdam, Germany.
⁷ School of Biological Sciences, University of Aberdeen, Aberdeen, UK.
⁸ Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK. Electronic address: fmurray@abdn.ac.uk.
⁹ The Rowett Institute, University of Aberdeen, Aberdeen, UK. Electronic address: lora.heisler@abdn.ac.uk.

PMID: 38653246
DOI: 10.1016/j.cmet.2024.03.016

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 the 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 that it is a promising pharmaceutical target for NAFLD treatment.

Keywords: G protein-coupled receptor; Gpr75; NAFLD; fatty liver; obesity; physical activity.