Mechanisms underlying the effects of the conditional knockdown of hepatic PCSK9 in attenuating lipopolysaccharide-induced acute liver inflammation

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is known to promote hyperlipidemia primarily by inducing the degradation of the low-density lipoprotein receptor. Notably, recent studies have demonstrated that PCSK9 promotes inflammation in the vascular system, however, the roles of PCSK9 in hepatic inflammation remain unclear. As PCSK9 is primarily expressed in the liver, this study aimed to elucidate the roles of PCSK9 and the underlying mechanisms in lipopolysaccharide (LPS)-challenged hepatocytes. Next-generation sequencing analysis revealed that the conditional knockdown of hepatic PCSK9 significantly reduced the plasma levels of total cholesterol and modulated the expression of hundreds of genes. Importantly, PCSK9 knockdown attenuated hepatic inflammation by suppressing several signaling pathways related to inflammation, including the Toll-like receptor, mitogen-activated protein kinase (MAPK), and phosphoinositide-3 kinase/protein kinase B pathways. This subsequently altered the expression of nuclear factor kappa-B and activator protein 1. The underlying mechanisms were further confirmed by in vitro studies using primary hepatocytes and HepG2 cells, with a p38MAPK inhibitor, a PCSK9 antibody, and two siRNAs against PCSK9. This study is the first to report that hepatic PCSK9 knockdown ameliorates LPS-induced acute liver inflammation via modulating multiple signaling pathways, thereby suggesting therapeutic potential of PCSK9 inhibitors in treating diseases related to hepatic inflammation.