Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies

被引:69
|
作者
Park, Hwan-Woo [1 ,2 ]
Lee, Jun Hee [2 ]
机构
[1] Konyang Univ, Coll Med, Dept Cell Biol, Taejon, South Korea
[2] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
关键词
autophagic flux; calcium channel blocker; high fat diet; lipotoxicity; NAFLD; obesity; protein inclusions; verapamil;
D O I
10.4161/15548627.2014.984268
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Nonalcoholic fatty liver disease (NAFLD), typically associated with overnutrition and obesity, is one of the most common liver diseases both in the US and worldwide. During obesity and NAFLD, lipotoxic injuries to hepatocytes can provoke formation of protein inclusions consisting of SQSTM1/p62 and ubiquitinated proteins. It has been suggested that autophagy deregulation during obesity contributes to protein inclusion formation and progression of other liver pathologies including insulin resistance, steatohepatitis, and hepatocellular carcinoma. To examine how lipotoxicity and obesity affect autophagy, we established an in vitro system where cultured HepG2 cells exhibit prominent accumulation of SQSTM1 and ubiquitinated proteins in insoluble inclusion bodies upon treatment with saturated fatty acids. Using this system and a mouse model of obesity, we have determined that obesity induces chronic elevation of cytosolic calcium levels in hepatocytes, which interferes with the fusion between autophagosomes and lysosomes. Intriguingly, pharmacological inhibition of calcium channels using the FDA-approved drug verapamil successfully restores autophagic flux and suppresses protein inclusions, not only in HepG2 cells but also in mouse liver. Verapamil also reduces hepatic lipid droplet accumulation, insulin resistance and steatohepatitis, suggesting that calcium channel blockers can be used for correction of general NAFLD pathologies. Indeed, there have been a number of clinical observations in which beneficial effects of calcium channel blockers against obesity-associated metabolic pathologies are observed in humans and animal models.
引用
收藏
页码:2385 / +
页数:2
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