Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers

• Published in: Nature communications Vol. 5; no. 1; p. 4834
• Main Authors: Park, Hwan-Woo, Park, Haeli, Semple, Ian A., Jang, Insook, Ro, Seung-Hyun, Kim, Myungjin, Cazares, Victor A., Stuenkel, Edward L., Kim, Jung-Jae, Kim, Jeong Sig, Lee, Jun Hee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.09.2014; Nature Publishing Group
• Subjects: 13; 13/1; 13/51; 13/95; 14; 14/1; 14/19; 14/34; 14/35; 631/154/436; 631/80/39; 692/699/2743/393; Animals; Autophagy - drug effects; Autophagy - physiology; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cytosol - metabolism; Echocardiography; Hep G2 Cells; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Immunoblotting; Immunohistochemistry; In Situ Nick-End Labeling; Lysosomes - metabolism; Metabolic Diseases - drug therapy; Metabolic Diseases - etiology; Metabolic Diseases - physiopathology; Mice; multidisciplinary; Obesity - complications; Phagosomes - metabolism; Science; Science (multidisciplinary); Verapamil - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms5834

Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo , we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome–lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients. Cellular defects in autophagy contribute to the development of fatty liver in obesity. Here, Park et al. reveal that hepatic autophagy is impaired by chronically elevated cytosolic calcium levels, and show that a clinically approved calcium channel blocker can improve metabolic parameters of obese mice.