ReviewArteriosclerosis, thrombosis, and vascular biology2026
Cytosolic Versus Lysosomal Lipolysis in Adipose Tissue: Opposing Roles in Cardiometabolic Disease.
Review in Arteriosclerosis, thrombosis, and vascular biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the 2 primary lipolytic systems in adipocytes: the canonical cytosolic pathway driven by ATGL/PNPLA2 (adipose triglyceride lipase) and the lysosomal pathway governed by LAL/LIPA (lysosomal acid lipase). We present emerging evidence that these pathways exert opposing effects in the context of obesity. While excessive fatty acid efflux from dysregulated cytosolic lipolysis is a known driver of adiposopathic dyslipidemia, adipose inflammation, and direct cardiac lipotoxicity, which collectively impair cardiometabolic health, the activity of the lysosomal pathway is emerging as a protective counterbalance. Genetic and pharmacological studies demonstrate that inhibiting cytosolic ATGL is beneficial for metabolic health, whereas enhancing LAL-mediated lipolysis mitigates obesity-related dysfunction. This functional antagonism between cytosolic and lysosomal lipolysis presents a new paradigm in lipid metabolism, suggesting that therapeutic strategies must be pathway-specific. We conclude that selectively inhibiting pathogenic cytosolic lipid release while promoting beneficial lysosomal lipid processing offers a nuanced approach to treating metabolic disease.
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