Lipidology, Volume 2, Issue 4 (December 2025) – 4 articles

ATP citrate lyase (ACL) is a highly conserved enzyme across eukaryotes that catalyzes the generation of cytosolic acetyl-CoA from citrate—a pivotal step linking central carbon metabolism to lipid biosynthesis. In the oleaginous yeast Yarrowia lipolytica, ACL is encoded by two genes, ACL1 and ACL2, forming a heteromeric complex that mirrors the multidomain architecture of the single-chain ACL enzymes found in mammals and plants. This conservation of catalytic architecture reflects a shared catalytic strategy across kingdoms, underscoring ACL’s fundamental role in metabolic integration. In Y. lipolytica, ACL is essential for directing mitochondrial citrate toward acetyl-CoA production and subsequent lipid accumulation. Yet, in contrast to well-characterized ACLs in animals and plants, the functional mechanisms and regulation of yeast ACL remain incompletely understood. A deeper understanding of ACL in Y. lipolytica offers not only evolutionary insights but also potential avenues for engineering lipid overproduction in microbial systems. Full article

In the last twenty years, an increasing volume of research has characterized lipids as dynamic signaling molecules that play essential roles in various physiological and pathological processes, especially concerning chronic diseases such as cardiovascular disorders, diabetes, liver disease, neurodegeneration, cancer, obesity, diabetic and chronic kidney diseases and atherosclerosis. Dysregulation of lipid synthesis and storage, lipolysis, fatty acid oxidation, lipid signaling pathways, and organelle-specific lipid modifications, including mitochondrial phospholipid remodeling and endoplasmic reticulum stress induced by saturated fatty acids, are recognized as contributors to the initiation and progression of this pathogenesis. Concurrently with the increasing comprehension of lipid metabolism, the last decade has seen progress in the understanding of genome control, especially with non-coding RNAs (ncRNAs). MicroRNAs, long non-coding RNAs, and circular RNAs, as ncRNAs, are essential modulators of gene expression at the epigenetic, transcriptional, and post-transcriptional levels that affect a number of lipid metabolism-related processes, such as fatty acid synthesis and oxidation, cholesterol homeostasis, and lipid droplet dynamics. Therapeutically, ncRNAs hold considerable promise owing to their tissue specificity and modularity, with antisense oligonucleotides and CRISPR-based editing currently under preclinical evaluation. In this context, we review recent studies exploring the interplay between ncRNAs and the regulatory networks governing lipid metabolism, and how disruptions in these networks contribute to chronic disease. This emerging paradigm underscores the role of ncRNA–lipid metabolism interactions as central nodes in metabolic and inflammatory pathways, highlighting the need for a holistic approach to therapeutic targeting. Full article

Background: Dyslipidaemia promotes atherosclerotic plaque formation. Plaques that are vulnerable to rupture have a higher proportion of inflammatory (M1:CD86) macrophages in their cap. Many plaque macrophages are derived from blood monocytes which have been exposed to elevated blood lipid levels. Here, we explored whether the inflammatory state of monocyte-derived macrophages is associated with blood lipid levels and assessed whether oxidised low-density lipoprotein (oxLDL) directly induces some of the observed changes. Method: Blood was collected from 20 individuals. Lipid profiles were measured, and monocytes differentiated into macrophages. Macrophage inflammatory state was assessed by flow cytometry for phenotypic markers (e.g., CD86 and CD163) and cytokine production: TNF, IL-1β, and IL-6. Furthermore, monocytes were isolated from 6 normo-lipidaemic individuals and cultured with oxLDL, followed by stimulation with LPS/IFNγ and assessment of the cytokine response. Results: The inflammatory phenotype acquired by macrophages (ex vivo) was related to levels of in vivo circulating lipids. Correlations for CD86/CD163 were found with CVD risk markers; most strongly with triglycerides (TG) and TG/HDL-C, but also with cholesterol/HDL-C and ApoB/ApoA1 and inversely with LDL particle size. Functionally, macrophage production of inflammatory cytokines (TNF and IL-1β) correlated with oxLDL levels and inversely with ApoA1. Macrophages differentiated from monocytes cultured with oxLDL produced significantly higher IL-1β but lower IL-10 (in response to LPS/IFNγ), compared to control cells. Conclusions: Monocyte-derived macrophages adopt an inflammatory phenotype relative to the levels of circulating lipid factors that are characteristic of atherogenic dyslipidaemia (such as high TG, TG/HDL-C and low LDL particle size), but not LDL-C. Full article

It has long been recognized that elevated circulating lipid levels are among the strongest risk factors for the development of plaques within the arterial wall that are characteristic of atherosclerotic cardiovascular disease. Indeed, decades of studies have identified the deposition of low-density lipoprotein as an initiator of this disease, which coordinates the vascular and immune dysfunction that fuels the advancement of the atherosclerotic plaque. However, in the vessel wall, deposited cholesterol and fatty acids are dynamic in nature and engage signaling pathways. Shifting from metabolic-related pathways, lipid modifications and their conversion to intermediates engage signaling cascades that further perpetuate the inflammatory milieu of the atherosclerotic plaque and its progression towards the fatal end-stage events associated with cardiovascular disease, including myocardial infarction. In this review, we will cover the cellular and molecular mechanisms that preserve homeostasis and advance disease, including how lipid species induce endothelial dysfunction and drive the development of macrophage foam cells. We will additionally discuss ongoing therapeutic strategies to combat the hyperlipidemia that underlies atherogenesis. Full article