Novel targets in the liver to treat cardiometabolic diseases

Abstract

Obesity is a growing worldwide epidemic, affecting more than 0.89 billion adults by 2022, and is projected to increase by nearly 70% by 2035. Consequently, the incidence of obesity-induced cardiometabolic diseases has markedly increased, becoming a major health problem and severely impacting quality of life and threatening long-term health outcomes worldwide, despite the availability of current therapeutic strategies. This highlights the urgent need for new treatment approaches. Therefore, in this thesis, we investigated novel therapeutic targets for combating cardiometabolic diseases, especially metabolic dysfunction-associated steatotic liver disease (MASLD) and atherosclerotic cardiovascular disease (ASCVD). As the liver is central in regulating lipid metabolism and inflammation, strongly affecting MASLD and ASCVD development, these targets were mainly liver-targeted. Overall, our findings revealed three novel therapeutic targets, including liver X receptor (LXR), hepatic lipase (HL), and ATP-binding cassette transporter A6 (ABCA6). Specifically, desmosterol-induced LXR activation via DHCR24 inhibition suppresses inflammation to prevent MASLD, while enhanced phospholipase activity of HL and abundance/activity of hepatic ABCA6 may reduce atherogenic lipids to decrease ASCVD. Collectively, this thesis provides valuable insights into the therapeutic potential of these targets, facilitating further investigation and accelerating their translational applications in humans for combating cardiometabolic diseases.