KMID : 0043320170400111336
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Archives of Pharmacal Research 2017 Volume.40 No. 11 p.1336 ~ p.1343
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Novel anti-adipogenic activity of anti-malarial amodiaquine through suppression of PPAR¥ã activity
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Kim Tae-Hee
Kim Hyo-Kyeong Hwang Eun-Sook
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Abstract
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Amodiaquine (AQ) was developed as a selective drug against Plasmodium falciparum malaria infection and has received increasing attention as a therapeutic agent for the treatment of rheumatoid arthritis, Parkinson¡¯s disease, and cancer due to its anti-inflammatory, anti-proliferative, and autophagic?lysosomal blockade properties. As autophagy activation is involved in promoting adipogenic differentiation, we examined whether anti-autophagic AQ affected adipocyte differentiation of 3T3-L1 pre-adipocytes. AQ dose-dependently and significantly suppressed adipocyte differentiation in conjunction with decreases in lipid droplet formation and expression of adipogenic markers including adiponectin, adipocyte fatty acid-binding protein 2 (aP2), resistin, and leptin. Although peroxisome proliferator-activated receptor ¥ã (PPAR¥ã) decreases by inhibition of autophagy, AQ treatment did not induce PPAR¥ã degradation despite the suppression of autophagolysosomal degradation. Instead, AQ suppressed the PPAR¥ã activity to transcriptionally activate the aP2 gene transcription through the selective prevention of nuclear localization of PPAR¥ã. These results demonstrated the novel anti-adipogenic activity of AQ and identified its underlying mechanism that AQ suppressed adipogenic gene expression and lipid formation by inhibiting nuclear localization of PPAR¥ã in an autophagy-independent manner. AQ is recommended as a safe and effective anti-obesity drug for controlling overweight and obesity.
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KEYWORD
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Amodiaquine, Adipocyte differentiation, Lipid accumulation, PPAR¥ã, Nuclear localization
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