Curcumin protects hepatic stellate cells against leptin-induced activation in vitro by accumulating intracellular lipids.
Obesity and type II diabetes mellitus are often associated with hyperleptinemia and commonly accompanied by nonalcoholic steatohepatitis, which could cause hepatic fibrosis. During hepatic fibrogenesis, the major effectors hepatic stellate cells (HSCs) become active, coupling with depletion of cellular lipid droplets and downexpression of genes relevant to lipid accumulation. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit HSC activation. We recently reported that leptin stimulated HSC activation, which was eliminated by curcumin, a phytochemical from turmeric. The current study was designed to explore the underlying mechanisms, focusing on their effects on the level of intracellular lipids. We hypothesized that one of the mechanisms by which leptin stimulated HSC activation was to stimulate the depletion of intracellular lipids, which could be abrogated by curcumin by inducing expression of genes relevant to lipid accumulation. In this report, we observed that leptin dose dependently reduced levels of intracellular fatty acids and triglycerides in passaged HSCs, which were eliminated by curcumin. The phytochemical abrogated the impact of leptin on inhibiting the activity of AMP-activated protein kinase (AMPK) in HSCs in vitro. The activation of AMPK resulted in inducing expression of genes relevant to lipid accumulation and increasing intracellular lipids in HSCs in vitro. In summary, curcumin eliminated stimulatory effects of leptin on HSC activation and increased AMPK activity, leading to inducing expression of genes relevant to lipid accumulation and elevating the level of intracellular lipids. These results provide novel insights into mechanisms of curcumin in inhibiting leptin-induced HSC activation.
Tang
Youcai
Y
Department of Pathology, School of Medicine, Saint Louis University, St. Louis, Missouri 63104, USA.
Chen
Anping
A
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008055:Lipids / Q000032:analysis / Q000737:chemistry; D008297:Male; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D022763:CCAAT-Enhancer-Binding Protein-alpha; D005227:Fatty Acids; D020738:Leptin; D008055:Lipids; D047495:PPAR gamma; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D055372:AMP-Activated Protein Kinases; D003474:Curcumin