Figure 4

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Figure 4

Spatiotemporal zonation and pathophysiology. (a) Examples of liver pathologies (gray) and their assignment to the lobular zones to which they are related. (b) Influence of the circadian rhythm on liver pathology. (a,b) Cholestasis promotes reprogramming of hepatocytes causing loss of metabolic function. Balancing WNT/β-catenin activity in zone 3 is critical to enable metabolic zonation while preventing unwanted proliferation and HCC formation. Temporal control of WNT/β-catenin signaling aligns pathway activity with the time when the β-catenin-regulated enzymes are required. Spatial imbalances in lipid metabolism, chronic jet lag, and eating high-caloric meals in the evening promote NAFLD/NASH. Extending fasting time prolongs fat burning. ALD and acute toxicities damage pericentral hepatocytes, causing cell death and loss of pericentral metabolic function. APAP toxicity is exacerbated in the beginning of the feeding cycle. Mouse studies suggested lower ischemic injury in the resting period. Abbreviations: ALD, alcoholic liver disease; APAP, acetaminophen; EtOH, ethyl alcohol; FA, fatty acid; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TG, triglyceride.

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Figure 4 Spatiotemporal zonation and pathophysiology. (a) Examples of liver pathologies (gray) and their assignment to the lobular zones to which they are related. (b) Influence of the circadian rhythm on liver pathology. (a,b) Cholestasis promotes reprogramming of hepatocytes causing loss of metabolic function. Balancing WNT/β-catenin activity in zone 3 is critical to enable metabolic zonation while preventing unwanted proliferation and HCC formation. Temporal control of WNT/β-catenin signaling aligns pathway activity with the time when the β-catenin-regulated enzymes are required. Spatial imbalances in lipid metabolism, chronic jet lag, and eating high-caloric meals in the evening promote NAFLD/NASH. Extending fasting time prolongs fat burning. ALD and acute toxicities damage pericentral hepatocytes, causing cell death and loss of pericentral metabolic function. APAP toxicity is exacerbated in the beginning of the feeding cycle. Mouse studies suggested lower ischemic injury in the resting period. Abbreviations: ALD, alcoholic liver disease; APAP, acetaminophen; EtOH, ethyl alcohol; FA, fatty acid; HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; TG, triglyceride. Copyright © 2023 by the author(s).

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