PI3K inhibition protects mice from NAFLD by down-regulating CMKLR1 and NLRP3 in Kupffer cells.

Inflammation induced by high-fat diet (HFD) is of critical importance in the development of hepatic steatosis. The role of chemerin in the progress of nonalcoholic fatty liver disease (NAFLD) remains controversial. Here, we have evaluated the effects and mechanism of chemerin on insulin sensitivity and inflammation. An inhibitor (wortmannin) and agonist (insulin-like growth factor 1 (IGF-1) of phosphatidyl inositol 3-kinase (PI3K) were applied to Kupffer cells (KCs) after treatment with a concentration gradient of chemerin in vitro. Mice were subjected to both HFD and intra-peritoneal injections of wortmannin and IGF-1 for 12 weeks. Levels of cytokines were evaluated by enzyme-linked immunosorbent assays and the mRNA and protein levels in the KCs were tested by quantitative real-time polymerase chain reaction and western blotting, respectively. Our data suggested that levels of interleukin 1β (IL-1β) and IL-18 in the KCs and mice treated with wortmannin were significantly lower than that of IGF-1. Consistently, the expression of chemokine-like receptor 1 (CMKLR1) and nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) was significantly lower in the KCs and mice treated with wortmannin than those treated with IGF-1. Consistently, liver function, insulin resistance, and hepatic steatosis were much more severe in mice treated with IGF-1 than those treated with wortmannin. In conclusions, PI3K inhibition attenuates hepatic steatosis and KC-mediated inflammation via down-regulation of CMKLR1 and NLRP3 in HFD mice.