Impact of Dysfunctional Protein Catabolism on Macrophage Cholesterol Handling

Author(s): Takuro Miyazaki*, Akira Miyazaki.

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 9 , 2019

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Protein catabolism in macrophages, which is accomplished mainly through autophagy- lysosomal degradation, ubiquitin-proteasome system, and calpains, is disturbed in atheroprone vessels. Moreover, growing evidence suggests that defects in protein catabolism interfere with cholesterol handling in macrophages. Indeed, decreases in autophagy facilitate the deposition of cholesterol in atheroprone macrophages and the subsequent development of vulnerable atherosclerotic plaques due to impaired catabolism of lipid droplets and limited efferocytic clearance of dead cells. The proteasome is responsible for the degradation of ATP-binding cassette transporters, which leads to impaired cholesterol efflux from macrophages. Overactivation of conventional calpains contributes to excessive processing of functional proteins, thereby accelerating receptor-mediated uptake of oxidized low-density lipoproteins (LDLs) and slowing cholesterol efflux. Furthermore, calpain-6, an unconventional nonproteolytic calpain in macrophages, potentiates pinocytotic uptake of native LDL and attenuates the efferocytic clearance of dead cells. Herein, we focus on recent progress in understanding how defective protein catabolism is associated with macrophage cholesterol handling and subsequent atherogenesis.

Keywords: Atherosclerosis, low-density lipoprotein, scavenger receptor, pinocytosis, efferocytosis, cholesterol efflux; ATP-binding cassette transporters.

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Year: 2019
Page: [1631 - 1643]
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DOI: 10.2174/0929867325666180326165234
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