Background: GLP-1 receptor agonist, such as exenatide, has been proven to attenuate nonalcoholic fatty liver disease (NAFLD) in vivo and in vitro. Its potential mechanism remains elusive. PNPLA3 is a major susceptibility gene for NAFLD and its I148M polymorphism increases the risk of all disorders of NAFLD spectrum. However, whether genetic variation contributes to variability in exenatide response is still unclear.
Methods: Wild type (I148I) PNPLA3 knockin cells were constructed using HepG2 as a template which are homozygous for the PNPLA3I148M mutation by CRISPR/Cas 9 gene editing technique. Oil Red O staining combined with TG quantification were used to evaluate lipid accumulation. Western blot and RT-qPCR were conducted respectively to measure the protein and mRNA expression of lipid synthesis and inflammatory markers.
Results: Lipid deposition was increased in both wild type (I148I) and mutant (I148M) HepG2 cells treated with palmitoleic acid (PA), while mutant cells had a higher TG content than wild type cells. Exenatide treatment was showed to be more efficacious in mutant cells than in wild type cells on reducing the accumulation of TG. Exenatide-mediated inhibition of SREBP-1 and endoplasmic reticulum stress pathway, and activation of AMPK pathway, were more significant in mutatnt cells than in wild type cells.
Conclusion: PNPLA3 I148M might modify the treatment response to exenatide in NAFLD. This research would provide a novel insight for individualized exenatide treatment.
Y. Chen: None.