Apolipoprotein E Mimetic Peptide-Mediated Modulation of Lipid Homeostasis

Lipid homeostasis is essential for maintaining cellular function and metabolic balance in all organisms, and its dysregulation can contribute to hypercholesterolemia, atherosclerosis, and cardiovascular disease. Adverse health outcomes are associated with elevated levels of low-density lipoprotein cholesterol (LDL-C), retention of which causes macrophages to transition into foam cells, leading to widespread inflammation, cardiovascular disease, and atherosclerosis. Statins (HMG-CoA reductase inhibitors) are considered the gold standard for LDL and very-low-density lipoprotein (VLDL) reduction, yet they exhibit side effects like myalgia and insulin resistance. Apolipoprotein E (apo E)-based lipid-binding synthetic mimetic peptides have been shown to clear cholesterol from the blood through canonical hepatic pathways such as HSPG receptors and are currently being studied to reduce plasma cholesterol. This review examines the development, biological properties, and therapeutic potential of the apo E mimetic peptide AEM-28. AEM-28 reduces atherogenic lipoproteins from plasma efficiently in multiple preclinical models as well as Phase I clinical trials in humans, where general tolerance of the treatment was observed. AEM-28 utilizes a unique mechanism of action that involves binding to atherogenic lipoproteins with multiple receptor-binding domains, facilitating enhanced clearance via the highly abundant heparan sulfate proteoglycans on hepatocytes. These attributes support the potential of AEM-28 as a complementary therapeutic or even an alternative for patients requiring LDL apheresis and those with hypercholesterolemia, atherosclerosis, or cardiovascular disease.