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Metabolically incompatible cell states become segregated in liver lobules, where hepatocytes organize across oxygen and nutrient gradients. Hepatocytes near the central vein (CV) experience low oxygen and maintain elevated glycolysis and triglyceride synthesis rates. CV-secreted R-spondin 3 sustains high WNT signaling and corresponding distinct transcriptional state by hepatocytes (green). In contrast, hepatocytes near portal triad (blue) exist in a low WNT environment, entering an alternative transcriptional state compatible with an oxygen-rich environment and optimized for beta-oxidation and gluconeogenesis.

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