IL6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease.
Academic Article
Overview
abstract
BACKGROUND & AIMS: A number of genetic polymorphisms have been associated with susceptibility to or protection against nonalcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD. METHODS: To enable mechanistic dissection, we developed a human pluripotent stem cells (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first adopted this liver culture to model NAFLD by utilizing a lipotoxic milieu reflecting the circulating levels of disease risk factors in patients. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotypes development. RESULTS: Our hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL6/STAT3 activity in liver cultures, consistent with transcriptomic data of liver biopsies from patients carrying the rs738409 SNP. Dampening IL6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, while boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-kB activity. CONCLUSIONS: Our study thus reveals a potential causal link between elevated IL6/STAT3 activity and 148M-mediated susceptibility to NAFLD. LAY SUMMARY: PNPLA3 I148M genetic variant increases the risk of NAFLD development and progression. To explore the underlying mechanism, we developed a hPSC-derived liver culture to study NAFLD by utilizing disease risk factors derived from patients. In liver cultures containing the variant, we observed that I148M variant increased the risk of NAFLD by elevating IL6/STAT3 signaling, which agreed with analysis of patient liver biopsies. Our findings demonstrate a potential causal link between elevated IL6/STAT3 activity and I148M variant-mediated risk of NALFD. Further, our liver culture is a useful platform for exploring genetic variants in NAFLD development.
