Liver Kinase B1 Links Macrophage Metabolism Sensing and Atherosclerosis
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Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol-laden macrophages at susceptible sites in the artery wall. Altered cellular metabolism plays an important role in the conversion of a macrophage into a lipid-laden foam cell and also in the ability of the macrophage to mount an inflammatory response. In the atherosclerotic lesion environment, the macrophage is exposed to a plethora of extracellular molecules that govern its phenotype, including cytokines, modified lipids, nutrients, and extracellular matrix components. Intracellular metabolic sensors allow the macrophage to adjust to the lesional environment and to alter its cellular functions accordingly. The molecular mechanisms underlying pathophysiological changes in the metabolism sensing machinery are not fully understood. In the current issue of Circulation Research,1 Liu et al enhance our understanding of foam cell formation by reporting that loss of expression of the metabolic sensor LKB1 (liver kinase B1) in macrophages results in increased uptake of modified lipoproteins, increased foam cell formation, and subsequently, increased atherosclerosis in 2 different mouse models. This study provides new links between macrophage metabolic sensing and atherosclerosis.
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LKB1, also known as STK11 (serine/threonine kinase 11), is a kinase originally identified as a tumor suppressor in patients with Peutz–Jeghers syndrome—an autosomal dominant genetic disorder associated with increased risk of developing cancer in the gastrointestinal tract and other organs.2 Later studies revealed that LKB1 acts in part as an upstream activator of AMPK (AMP-activated protein kinase)—an intracellular energy sensor activated by low nutrient status in cells as a mechanism to preserve energy.3 However, LKB1 also has AMPK-independent targets in cells. Recent studies have shown that the LKB1/AMPK pathway is activated by glucose deprivation and that reduced levels of the glycolytic intermediate fructose-1,6-bisphosphate …