Hesperetin is a potent bioactivator that activates SIRT1-AMPK signaling pathway in HepG2 cells
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ORIGINAL ARTICLE
Hesperetin is a potent bioactivator that activates SIRT1-AMPK signaling pathway in HepG2 cells Hajar Shokri Afra 1 & Mohammad Zangooei 1,2 & Reza Meshkani 1 & Mohammad Hossein Ghahremani 3 & Davod Ilbeigi 4 & Azam Khedri 1 & Shiva Shahmohamadnejad 1 & Shahnaz Khaghani 1 & Mitra Nourbakhsh 5 Received: 11 September 2018 / Accepted: 20 March 2019 / Published online: 15 May 2019 # University of Navarra 2019
Abstract Sirtuin 1 (SIRT1) is a deacetylase enzyme that plays crucial roles in controlling many cellular processes and its downregulation has been implicated in different metabolic disorders. Recently, several polyphenols have been considered as the effective therapeutic approaches that appear to influence SIRT1. The main goal of this study was to evaluate the effect of hesperetin, a citrus polyphenolic flavonoid, on SIRT1 and AMP-activated kinase (AMPK). HepG2 cells were treated with hesperetin in the presence or absence of EX-527, a SIRT1 specific inhibitor, for 24 h. Resveratrol was used as a positive control. SIRT1 gene expression, protein level, and activity were measured by RT-PCR, Western blotting, and fluorometric assay, respectively. AMPK phosphorylation was also determined by Western blotting. Our results indicated a significant increase in SIRT1 protein level and activity as well as an induction of AMPK phosphorylation by hesperetin. These effects of hesperetin were abolished by EX-527. Furthermore, hesperetin reversed the EX-527 inhibitory effects on SIRT1 protein expression and AMPK phosphorylation. These findings suggest that hesperetin can be a novel SIRT1 activator, even stronger than resveratrol. Therefore, the current study may introduce hesperetin as a new strategy aimed at upregulation SIRT1-AMPK pathway resulting in various cellular processes regulation. Keywords Hesperetin . Polyphenol . SIRT1 . AMPK . HepG2
Abbreviations ACAT acyl-CoA:cholesterol acyltransferase AMPK AMP-activated protein kinase HST Hesperetin LKB1 Liver Kinase B1
* Shahnaz Khaghani [email protected] * Mitra Nourbakhsh [email protected] 1
Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2
Department of Biochemistry, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
3
Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
4
Neuroscience Research Center, Torbat Heydarieh University of medical science, Torbat Heydarieh, Iran
5
Department of Clinical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
LXRs NAD+ NAM NAMPT NF-κB PGC-1α PMF PPAR RSV ROS SIRT1 SREBPs STACs TNF-α
Liver X receptors Nicotinamide adenine dinucleotide Nicotinamide Nicotinamide phosphoribosyl transferase Nuclear factor κB PPAR-γ co-activator 1α Polymethoxylated flavones Peroxisome proliferator-activated receptor Resveratrol Reactive oxygen species Sirtuin 1 Sterol regulatory element-binding proteins Sirtuin activating compounds Tumor necro
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