AMPK-mediated HMGCR regulation of cholesterol metabolism in macrophages

Title: AMPK-mediated HMGCR regulation of cholesterol metabolism in macrophages
Authors: Burkovsky, Leah
LeBlond, Nicholas D.
Yaworski, Rebecca A.
Margison, Kaitlyn D.
Fullerton, Morgan D.
Date: 2017
Abstract: Atherosclerosis, the accumulation of cholesterol-loaded macrophages (foam cells) in the arteries, leads to cardiovascular disease, which is the leading cause of mortality in the developed world. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the rate-liming step in cholesterol biosynthesis and is regulated by several mechanisms, including inhibition by reversible phosphorylation by the energy-sensing AMP-activated protein kinase (AMPK). AMPK activators are under investigation for their potential as antiatherogenic agents. The purpose of this project was to test the physiological significance of AMPK regulating HMGCR activity in macrophages. Using bone marrow-derived macrophages from HMGCR knock-in (KI) mice, where the phosphorylation site had been eliminated, this project investigated the impact that AMPK signaling to HMGCR has on cholesterol synthesis, accumulation of cholesterol, and cholesterol efflux. Since atherosclerosis is tightly linked with inflammation in plaques, cytokine expression was also assessed after treating macrophages with a pro-inflammatory stimulus. While there was increased cholesterol synthesis in macrophages from HMGCR KI mice than wild-type (WT) mice, there were no differences between WT and HMGCR KI macrophages in all the other aspects examined. This suggests that the regulation of HMGCR through phosphorylation by AMPK is not physiologically significant to the development of atherosclerosis. Further investigation is required in vivo to confirm this finding. To further understand how AMPK activators may be a potential drug strategy for treating atherosclerosis, other pathways and mechanisms need to be investigated.
CollectionBiochimie, microbiologie et immunologie // Biochemistry, Microbiology and Immunology