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, that is, increased levels of plasma low-density lipoprotein (LDL) and oxidized LDL (ox-LDL). Approximately one-third of NASH develops hepatic fibrosis. The role of hypercholesterolemia in T2DM and 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 the role of ox-LDL in activation of HSCs, to assess curcumin effects on eliminating the role of ox-LDL, and to further explore the underlying mechanisms. In this report, we observe that ox-LDL alters the 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 (PPARgamma). 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 by interrupting Wnt signaling and stimulating PPARgamma activity. These results provide novel insights into the role of ox-LDL in T2DM and NASH-associated hepatic fibrogenesis and mechanisms by which curcumin suppresses ox-LDL-induced HSC activation, as well as the implication of curcumin in the treatment of T2DM and NASH-associated hepatic fibrosis.
Kang
Qiaohua
Q
Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO 63104, USA.
Chen
Anping
A
D000818:Animals; D015153:Blotting, Western; D004396:Coloring Agents / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism; D008297:Male; D016297:Mutagenesis, Site-Directed; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051131:Receptors, Oxidized LDL / Q000235:genetics*
D004396:Coloring Agents; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D051131:Receptors, Oxidized LDL; C099252:oxidized low density lipoprotein; D003474:Curcumin