Lipidology

Atherosclerosis is a progressive cardiovascular disease characterized by lipid accumulation, oxidative stress, and inflammation within the arterial walls. Environmental pollutants, including particulate matter (PM), diesel exhaust particles (DEPs), and heavy metals, contribute directly to the initiation and progression of arterial plaques by promoting LDL oxidation, endothelial dysfunction, foam cell formation, and vascular inflammation, whilst high-density lipoprotein (HDL) provides protective effects. This review examines the mechanistic links between environmental exposures, lipid dysregulation, and plaque formation, highlighting how both gaseous and particulate pollutants and toxic and essential metals, as well as endocrine disrupting chemicals, influence atherosclerotic risk. Potential antioxidant and lifestyle interventions to mitigate these pollutant-driven effects are also discussed.

Lipids are a diverse group of hydrophobic molecules including fats, oils, phospholipids, and steroids that are vital for numerous biological functions including energy storage, cellular structure, and signaling whose composition and metabolism undergo profound transformations with age. These age-related shifts due to increased lipid peroxidation, disrupted cholesterol homeostasis, and altered membrane phospholipid content, actively contribute to progressive loss in cellular homeostasis and pathogenesis of major age-related diseases. This review explores the critical role of lipids: as master regulators of cellular signaling pathways, and as key drivers of chronic inflammation and metabolic dysfunction. Dysregulated lipid metabolism is central to cardiovascular disease which is driven by altered myocardial energy substrate utilization and lipoprotein dynamics. In neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, disruptions in ceramide, cholesterol, and specialized pro-resolving lipid mediators fuel neuroinflammation and protein aggregation. Furthermore, we explore the dual role of dietary lipids, which can either exacerbate or mitigate age-related decline, highlighting the potential of personalized nutritional approaches and lipid-targeting therapeutics. By integrating the mechanisms of lipid signaling, inflammation, and metabolic regulation, this analysis highlights that lipids are not merely passive structural components but active drivers of the aging process, positioning lipid metabolism as a promising frontier for interventions aimed at promoting health span and combating age-related disease.

Cardiovascular disease is the leading cause of mortality in insulin-resistant individuals, with metabolic cardiomyopathy preceding overt heart failure in a substantial proportion of patients with diabetes. Skeletal muscle accounts for approximately 40% of body mass and nearly 80% of insulin-stimulated glucose disposal, positioning it as a major determinant of systemic lipid flux. Dysregulation of lipid droplet dynamics, lipolysis, and fatty acid trafficking in skeletal muscle alters circulating lipid availability and promotes ectopic lipid deposition and mitochondrial stress in the myocardium. Intramyocellular lipid handling is governed by coordinated actions of lipid droplets, perilipin proteins (PLIN2 and PLIN3), adipose triglyceride lipase (ATGL), and diacylglycerol acyltransferases (DGAT1/2), which together regulate the rate and composition of fatty acid release into the circulation. Impaired coupling between intramyocellular lipid droplet turnover and mitochondrial oxidation in insulin-resistant muscle increases circulating free fatty acids, reducing cardiac oxidative capacity. In response, the myocardium undergoes mitochondrial lipid remodeling, including alterations in cardiolipin composition that impair cristae structure and electron transport chain efficiency. Excess lipid exposure activates apoptosis signal-regulating kinase-1 (ASK-1), promoting cardiomyocyte apoptosis and inflammatory signaling, while peroxisome proliferator-activated receptor gamma (PPARγ) modulates lipid uptake, storage, and mitochondrial oxidation in a context-dependent manner. This review integrates skeletal muscle–cardiac lipid crosstalk with ASK-1 and PPARγ signaling to define mechanisms linking peripheral insulin resistance to early myocardial dysfunction and to identify targets for intervention before irreversible cardiac remodeling develops.