DOI: 10.1161/jaha.126.050155 ISSN: 2047-9980

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

Farnaz Oghbaei, Maryam Musavi, Mohammad Abavisani, Ramin Raoufinia, Ahmad Ghasemi, Amir Abbas Momtazi‐Borojeni
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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.

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