Role of Lipin-1 in Macrophage-Mediated Atherosclerosis: Is It Atherogenic or Atheroprotective?

Macrophages are central regulators of atherosclerosis, governing lipid accumulation, inflammatory signaling, and plaque stability. Lipin-1 is a multifunctional lipid-metabolic regulator that integrates cellular metabolism with inflammatory responses through its dual roles as a phosphatidic acid phosphatase enzyme and a transcriptional coregulator. However, its role in macrophage-driven atherosclerosis remains controversial. This review critically evaluates the domain-specific functions of lipin-1 and their impact on disease progression. Accumulating evidence indicates that lipin-1 exerts divergent, domain-dependent effects. The transcriptional coregulatory activity of lipin-1 promotes peroxisome proliferator-activated receptor/peroxisome proliferator-activated receptor γ coactivator 1-α signaling, enhances fatty acid β-oxidation and oxidative phosphorylation, and supports interleukin-4-driven proresolving macrophage polarization. It also enhances efferocytosis, suppresses sterol regulatory element-binding protein-mediated lipogenesis, and reduces oxidized low-density lipoprotein-induced foam-cell formation. These effects are associated with reduced necrotic core formation, lower interleukin-23 signaling, diminished macrophage necroptosis, and improved plaque stability in experimental models. In contrast, the phosphatidic acid phosphatase enzymatic activity of lipin-1 activates diacylglycerol-dependent protein kinase C-extracellular signal-regulated kinase- activator protein-1 and toll-like receptor 4 signaling, promotes inflammatory eicosanoid production, enhances oxidized low-density lipoprotein uptake, impairs cholesterol efflux, and accelerates foam-cell formation and vascular inflammation. Myeloid-specific loss of phosphatidic acid phosphatase activity reduces lesion size and inflammatory burden while improving macrophage lipid handling. Collectively, current evidence supports a domain- and context-dependent role for lipin-1 in atherosclerosis. The transcriptional coregulatory function appears predominantly atheroprotective, whereas phosphatidic acid phosphatase enzymatic activity is proinflammatory and atherogenic. Selective modulation of lipin-1 activity in macrophages may therefore represent a promising therapeutic strategy to limit atherosclerosis progression while preserving inflammation-resolving pathways.