Curcumin suppresses expression of low-density lipoprotein (LDL) receptor, leading to the inhibition of LDL-induced activation of hepatic stellate cells.
OBJECTIVE
Obesity is often accompanied by hypercholesterolemia characterized by elevated levels of plasma low-density lipoprotein (LDL) and associated with non-alcoholic steatohepatitis, which could progress to hepatic fibrosis. Hepatic stellate cells (HSCs) are the major effectors of hepatic fibrogenesis. This study aims to clarify effects of LDL on activation of HSC, to evaluate roles of curcumin in suppressing these effects and to further elucidate the underlying molecular mechanisms.


METHODS
HSCs were prepared from rats and cell proliferation was measured by cell proliferation assays (MTS assays). Transient transfection assays were performed to evaluate gene promoter activities. Real-time polymerase chain reaction and Western blotting were used to analyse the expression of genes.


RESULTS
LDL stimulated HSC activation in vitro, which was attenuated by curcumin. Curcumin reduced the abundance of LDL receptor (LDLR) in activated HSCs, decreasing cellular cholesterol. Curcumin-dependent activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) differentially regulated the expression of the transcription factors, sterol regulatory element-binding proteins (SREBPs), in activated HSCs, resulting in the suppression of LDLR gene expression.


CONCLUSIONS
Curcumin suppressed LDLR gene expression in activated HSCs in vitro by activating PPARgamma and differentially regulating gene expression of SREBPs, reducing cellular cholesterol and attenuating the stimulatory effects of LDL on HSC activation. These results provide novel insights into the roles and mechanisms of curcumin in the inhibition of LDL-induced HSC activation. This curcumin, a constituent of turmeric, may be useful in preventing hypercholesterolemia-associated hepatic fibrogenesis.
Kang
Qiaohua
Q
Department of Pathology, School of Medicine, Saint Louis University, St. Louis, MO 63104, USA.
Chen
Anping
A
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
D047495:PPAR gamma; D011973:Receptors, LDL; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D003474:Curcumin