HMGCR enzyme deficiency-induced alterations in cellular energy metabolism pathways (mitoHMGCR)

HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is an enzyme that plays a crucial role in cholesterol biosynthesis. Research on HMGCR is important for numerous patients with atherosclerosis because inhibiting the enzyme with statins has been shown to reduce the risk of cardiovascular events such as heart attacks and strokes. Despite being generally well tolerated, statin intolerance is reported in 5-30% of patients, leading to reduced regimen adherence and statin therapy duration. In addition, HMGCR may also have a role in the development of diabetes.

The goal of the Project is to identify disease mechanisms and discover molecular pathways linking excessive inhibition of HMGCR and hepatotoxicity and myopathy. We will use a unique HMGCR-KO mouse model to address important gaps in knowledge about HMGCR-linked cellular energy metabolism pathways and statin pharmacology. We will map the molecular effects of HMGCR deficiency, thus advancing the understanding of mechanisms behind the statin treatment-induced tissue-specific effects. We will specifically explore effects of HMGCR on liver cells and its involvement in the insulin resistance mechanisms. All this will help to evaluate the hypothesis of HMGCR as a crucial enzyme for maintaining energy metabolism balance and to drive discovery of innovative approaches to prevent and treat cardiometabolic diseases.