KPNβ1 promotes palmitate-induced insulin resistance via NF-κB signaling in hepatocytes

It has been intensively studied that inflammation contributes to the insulin resistance development in obesity-induced type 2 diabetes mellitus (T2DM). In this study, we assessed the effect of karyopherin beta 1 (KPN beta 1) in hepatic insulin resistance and the underlying mechanisms using high-fat diet (HFD) fed mice and palmitate (PA)-stimulated hepatocytes (HepG2). KPN beta 1 expression is increased in the HFD fed mice liver. PA upregulated KPN beta 1 expression in HepG2 cells in a time-dependent manner. PA also increased pro-inflammatory cytokines expression, including tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and interleukin 1 beta (IL-1 beta). KPN beta 1 knockdown reversed PA-induced pro-inflammatory cytokines expression and insulin-stimulated glucose uptake in HepG2 cells. In addition, KPN beta 1 knockdown reduced intracellular lipid accumulation. Mechanistically, KPN beta 1 transports nuclear factor kB (NF-kappa B) p65 from the cytoplasm to the nucleus to increase pro-inflammatory genes expression. In summary, KPN beta 1 acts as a positive regulator in the NF-kappa B pathway to enhance palmitate-induced inflammation response and insulin resistance in HepG2 cells.