PNPLA3 I148M is involved in the variability in anti-NAFLD response to exenatide.

PURPOSE: GLP-1 receptor agonists, such as exenatide, have been proven to attenuate nonalcoholic fatty liver disease (NAFLD) in vivo and in vitro. However, the efficiency of exenatide had interindividual differences. PNPLA3 is a major susceptibility gene for NAFLD and its I148M polymorphism increases the risk of all disorders of the NAFLD spectrum. Whether this variant contributes to variability in exenatide response is still unclear. METHODS: PNPLA3 148I knockin HepG2 cells were constructed using the Cas9/sgRNA system. Oil Red O staining combined with TG quantification was used to evaluate lipid accumulation. Western blotting and qRT-qPCR were conducted, respectively, to measure the protein and mRNA expression of lipid metabolic and endoplasmic reticulum (ER) stress-related inflammatory markers. PNPLA3 I148M was genotyped in type 2 diabetics using Sanger sequencing. The exenatide-induced changes in liver fat content and other clinical parameters were compared between PNPLA3 I148M genotypes. RESULTS: Lipid deposition increased in both PNPLA3 148I/I and 148M/M HepG2 cells treated with palmitoleic acid, while cells with 148M/M had a higher TG content than those with 148I/I. Exendin-4 treatment was showed to be more significant in 148I/I cells than in 148M/M cells in terms of reducing the intrahepatic fat content, inhibiting SREBP-1c and ER stress-related inflammation, and activating AMPK-ACC lipid oxidation pathway. In patients with type 2 diabetes, 24-week treatment with exenatide improved liver fat content in patients carrying PNPLA3 148I/I better than in patients with 148M/M. CONCLUSIONS: PNPLA3 I148M might modify the anti-NAFLD response to exenatide.