The role of AMP-activated kinase in suppressing atherosclerosis

Summary The main objective of this project is to study how AMPK controls cholesterol production in the liver and macrophages. AMPK’s activation in response to exercise is thought to be part of the protective mechanism against the development of heart disease. We aim to investigate whether by changing the activity of AMPK, using drugs that currently in clinical trial, we can augment the body’s natural control mechanisms and significantly reduce the development of atherosclerosis.

Project Details

Stemming from dyslipidemia and maladaptive inflammatory responses, atherosclerosis precedes and predicts the development of cardiovascular complications including stroke and myocardial infarction, which account for more than 30% of all deaths worldwide. AMP-activated kinase (AMPK) is a key regulator of whole body energy metabolism, including lipid metabolism, glucose uptake and mitochondrial biogenesis. It has been shown that the suppression of AMPK activity under conditions of chronic over-nutrition may contribute to the development of metabolic diseases. We have recently shown that activation of the regulatory enzyme AMPK reduces cholesterol production in a way similar to statin therapy (Loh et.al 2019 Hepatology Communications). The main objective of this project is to study how AMPK controls cholesterol production in the liver and macrophages. AMPK’s activation in response to exercise is thought to be part of the protective mechanism against the development of heart disease. We aim to investigate whether by changing the activity of AMPK, using drugs that currently in clinical trial, we can augment the body’s natural control mechanisms and significantly reduce the development of atherosclerosis. Since reduction of AMPK activity was found in response to hyperglycemia, the project also aims to shed light on whether impairment of AMPK signaling responsible toward the pathology of diabetes-associated atherosclerosis. We hypothesize that pharmacological activation of the signaling cascade which culminates in AMPK activation may serve as an alternative cholesterol lowering therapy and reducing atherosclerosis development.