Precision and efficacy guided novel approaches to target dyslipidemia and atherosclerosis

Abstract

This thesis explores innovative therapeutic strategies to more effectively treat obesity and its associated cardiometabolic diseases. Despite scientific and medical progress, obesity and related conditions such as type 2 diabetes and atherosclerotic cardiovascular disease continue to rise globally. Here, we focus on three promising strategies to combat these diseases: 1) targeting the right tissue, 2) multi-targeted approaches, and 3) refinement of intracellular signalling pathways.

First, the work examines microRNAs, particularly miR-33a, as potential multi-targeting tools to improve cholesterol homeostasis and reduce atherosclerosis. The studies show how modulating miR-33a affects lipid metabolism through coordinated regulation of several key proteins. The importance of tissue specificity is highlighted by demonstrating that liver-targeted inhibition of ANGPTL4 lowers plasma lipids and attenuates atherosclerosis, without the adverse effects seen with systemic inhibition. The dissertation also investigates the neuroplasticity gene DCL, expressed in hypothalamic β-tanycytes, revealing its subtle yet significant role in whole-body energy balance and white adipose tissue browning. Finally, the thesis evaluates biased GLP-1 receptor agonism as a means to optimize downstream signalling and improve the metabolic effects of obesity pharmacotherapy.

Together, these findings provide new insights into how precision targeting and pathway refinement can enhance the efficacy and tolerability of therapies for obesity-related diseases.