The following is a summary of the “IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease,” published in the January 2023 issue of Journal of Journal of Hepatology by Park, et al.

Many genetic variants have been linked to either increased or decreased risk of developing non-alcoholic fatty liver disease (NAFLD), although the processes behind these associations are unclear. In this study, we zeroed in on the rs738409 C>G SNP, which results in the I148M variation of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is highly linked to NAFLD. They created a human pluripotent stem cell (hPSC)-derived multicellular liver culture by adding hPSC-derived hepatocytes, hepatic stellate cells, and macrophages to facilitate mechanistic dissection. They initially used this liver culture to model NAFLD by exposing the cells to a lipotoxic environment that mimics the amounts of disease risk factors found in the blood of people with NAFLD. 

They then evaluated the progression of the NAFLD phenotype between two isogenic pairs of liver cultures that differed solely at the rs738049 locus. Lipid accumulation, oxidative stress, inflammation, and stellate cell activation were all faithfully reproduced in our hPSC-derived liver culture, which are all hallmarks of NAFLD’s onset and progression. The I148M variant promoted the progression of NAFLD phenotypes in response to lipotoxic circumstances. Liver biopsies from people bearing the rs738409 SNP showed transcriptome data consistent with increased IL-6/signal transducer and activator of transcription 3 (STAT3) activity in culture. 

Reducing IL-6/STAT3 activity reduced I148M-mediated vulnerability to NAFLD, but increasing IL-6/STAT3 activity in wild-type liver cells promoted NAFLD development. Finally, we found that the rs738409 SNP boosted NF-kappaB activity in liver cultures, explaining the heightened IL-6/STAT3 activity. In conclusion, our results suggest that increased IL-6/STAT3 activity is causally related to 148M-mediated susceptibility to NAFLD.