title: Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling.
abstract: Non-alcoholic steatohepatitis (NASH) is a major risk factor for hepatic fibrogenesis. NASH is often found in diabetic patients with hyperglycemia. Hyperglycemia induces non-enzymatic glycation of proteins, yielding advanced glycation end-products (AGEs). Effects of AGEs are mainly mediated by two categories of cytoplasmic membrane receptors. Receptor for AGEs (RAGE) is associated with increased oxidative stress and inflammation, whereas AGE receptor-1 (AGE-R1) is involved in detoxification and clearance of AGEs. Activation of hepatic stellate cells (HSC) is crucial to the development of hepatic fibrosis. We recently reported that AGEs stimulated HSC activation likely by inhibiting gene expression of AGE-R1 and inducing gene expression of RAGE in HSC, which were eliminated by the antioxidant curcumin. This study is to test our hypothesis that curcumin eliminates the effects of AGEs on the divergent regulation of the two receptors of AGEs in HSC by interrupting the AGE-caused activation of leptin signaling, leading to the inhibition of HSC activation. We observed herein that AGEs activated leptin signaling by inducing gene expression of leptin and its receptor in HSC. Like AGEs, leptin differentially regulated gene expression of RAGE and AGE-R1. Curcumin eliminated the effects of AGEs in HSC by interrupting leptin signaling and activating transcription factor NF-E2 p45-related factor 2 (Nrf2), leading to the elevation of cellular glutathione and the attenuation of oxidative stress. In conclusions, curcumin eliminated the effects of AGEs on the divergent regulation of gene expression of RAGE and AGE-R1 in HSC by interrupting the AGE-caused activation of leptin signaling, leading to the inhibition of HSC activation.
authors.affiliation: Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA.
authors.forename: Anping
authors.initials: A
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002867:Chromones; D030024:Curcuma; D003474:Curcumin / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D008103:Liver Cirrhosis / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism; D020032:Tyrphostins
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D017127:Glycation End Products, Advanced; D020738:Leptin; D009025:Morpholines; D010936:Plant Extracts; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D054411:Receptors, Leptin; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003474:Curcumin