Here, we demonstrated that conditional knockdown of hepatic PCSK9 significantly decreased hyperlipidemia-induced gene expression and protein levels of some key pro-inflammatory factors potentially via downregulating several signaling pathways including TLR/MyD88, MAPK, and PI3K/AKT; this phenomenon further decreased the phosphorylation levels of NF-κB and AP-1 proteins in the nuclei, resulting in a reduction in inflammatory reaction. The gene discussed is MYD88; the disease is hyperlipidemia.