Genetic Evidence for GLP-1 and GIP Receptors as Targets for Treatment and Prevention of MASLD/MASH

Ran Yan; Lu Liu; Ioanna Tzoulaki; Jiangao Fan; Giovanni Targher; Zhongshang Yuan; Jian Zhao

doi:10.1111/liv.16150

Genetic Evidence for GLP-1 and GIP Receptors as Targets for Treatment and Prevention of MASLD/MASH

Liver Int. 2024 Nov 2. doi: 10.1111/liv.16150. Online ahead of print.

Authors

Ran Yan^{1

2}, Lu Liu^{3

4}, Ioanna Tzoulaki^{5

6}, Jiangao Fan⁷, Giovanni Targher^{8

9}, Zhongshang Yuan^{1

2}, Jian Zhao^{10

11}

Affiliations

¹ Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
² Institute for Medical Dataology, Shandong University, Jinan, Shandong, China.
³ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Centre for Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁷ Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ Department of Medicine, University of Verona, Verona, Italy.
⁹ Metabolic Diseases Research Unit, IRCCS Sacro Cuore-Don Calabria, Negrar di Valpolicella, Verona, Italy.
¹⁰ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
¹¹ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

PMID: 39487684
DOI: 10.1111/liv.16150

Abstract

Background and aims: Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty.

Methods: We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits.

Results: Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (OR_GLP-1 = 0.168 [95% CI 0.033-0.839], p = 0.030; OR_GIP = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10^-8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531-0.849], p = 9.07 × 10^-4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD-related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index.

Conclusions: GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.

Keywords: drug target; glucagon‐like peptide‐1; glucose‐dependent insulinotropic polypeptide; metabolic dysfunction‐associated steatotic liver disease.

Abstract

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