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Published on: April 16, 2019
Evaluating the efficacy of GIPR agonists on non-alcoholic fatty liver disease: A Mediation Mendelian Randomization
Siyuan Xie1, Delong Chen2, Yangke Cai1
1Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China.
Objective:
Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide while still lacks drugs for treatment or prevention. We aimed to investigate the causal role of glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) on NAFLD and identify the mediated risk factors by which GIPRAs exert their therapeutic effects.
Methods:
Genetic proxies of GIPRAs were identified as cis-SNPs of GIPR associated with both the gene expression level and HbA1c and analyses including colocalization and linkage disequilibrium (LD) were performed for validation. We then performed two-sample two-step mendelian randomization to determine the causal effect of GIPRAs on NAFLD.
Results:
The MR analysis suggested genetic proxies of GIPRAs were causally associated with reduced risk of NAFLD (Odds ratio (OR): 0.46, 95 % confidence interval (95 % CI): 0.24-0.88, P = 0.02) and T2DM (OR: 0.10, 95 % CI: 0.07-0.13, P < 0.01). In addition, Mediation analysis showed evidence of indirect effect of GIPRAs on NAFLD via TRIG (0.88, [0.85-0.92], P < 0.01) and HDL-C (0.85, [0.80-0.90], P < 0.01).
Conclusions:
Our study provided strong evidence to support the causal role of GIPRAs on reducing the risk of NAFLD probably through improving lipid metabolism, especially TG and HDL-C, providing guidance for future clinical trials.
Insights
Glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) show a causal role in reducing non-alcoholic fatty liver disease (NAFLD) risk. This effect is likely mediated by improvements in triglyceride and HDL-C levels.
Area of Science:
- Metabolic disease research
- Hepatology
- Pharmacogenomics
Background:
- Non-alcoholic fatty liver disease (NAFLD) is a prevalent global health concern lacking targeted therapies.
- Emerging therapeutic targets include agents modulating glucose metabolism and related pathways.
Purpose of the Study:
- To investigate the causal relationship between glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) and NAFLD.
- To identify potential mediating factors through which GIPRAs exert their effects on NAFLD risk.
Main Methods:
- Utilized Mendelian randomization (MR) with genetic proxies for GIPRAs.
- Employed cis-SNPs of the GIPR gene associated with gene expression and HbA1c.
- Performed colocalization and linkage disequilibrium analyses for validation.
Main Results:
- Genetic proxies of GIPRAs demonstrated a significant causal association with reduced NAFLD risk (OR: 0.46).
- GIPRAs were also causally linked to a lower risk of type 2 diabetes mellitus (T2DM) (OR: 0.10).
- Mediation analysis indicated indirect effects of GIPRAs on NAFLD via improvements in triglycerides (TG) and HDL-cholesterol (HDL-C).
Conclusions:
- This study provides robust evidence for a causal role of GIPRAs in mitigating NAFLD risk.
- The therapeutic effects of GIPRAs on NAFLD appear to be mediated by improved lipid metabolism, specifically TG and HDL-C levels.
- Findings offer valuable insights for future clinical trials investigating GIPRA-based therapies for NAFLD.
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