Curcumin eliminates oxidized LDL roles in activating hepatic stellate cells by suppressing gene expression of lectin-like oxidized LDL receptor-1

Type II diabetes mellitus (T2DM) is often accompanied by non-alcoholic steatohepatitis (NASH) and associated with hypercholesterolemia, i.e. increased levels of plasma low-density lipoprotein (LDL) and oxidized LDL (ox-LDL). Approximately one third of NASH develops hepatic fibrosis. The hypercholesterolemia role in T2DM & NASH-associated hepatic fibrogenesis remains obscure. We previously reported that the phytochemical curcumin inhibited the activation of hepatic stellate cells (HSCs), the major effector cells during hepatic fibrogenesis, and protected the liver from fibrogenesis in vitro and in vivo. The aims of this study are to evaluate ox-LDL roles in activation of HSCs, to assess curcumin effects on eliminating the ox-LDL roles, and to further explore the underlying mechanisms. In this report, we observe that ox-LDL alters expression of genes closely relevant to HSC activation, which is eliminated by curcumin. Curcumin suppresses gene expression of lectin-like oxidized LDL receptor-1 (LOX-1), leading to the blockade of the transport of extracellular ox-LDL into cells. This suppressive effect of curcumin results from the interruption of Wnt signaling and the activation of peroxisome proliferator-activated receptor-gamma (PPARγ). In conclusion, these results support our initial hypothesis and demonstrate that ox-LDL stimulates HSC activation, which is eliminated by curcumin by suppressing lox-1 expression via interrupting Wnt signaling and stimulating PPARγ activity. These results provide novel insights into roles of ox-LDL in T2DM & NASH-associated hepatic fibrogenesis and mechanisms by which curcumin suppresses ox-LDL-induced HSC activation, as well as the implication of curcumin in treatment of T2DM & NASH-associated hepatic fibrosis.