The liver, a large organ located in the upper right abdomen, performs many functions, from metabolizing nutrients to detoxifying harmful substances. This versatility is partly due to liver zonation, a unique organizational principle. Zonation refers to the functional specialization of liver cells based on their location within the liver’s microscopic architecture.
Understanding Liver Zonation
Liver zonation describes the differential distribution of metabolic functions and gene expression across the liver lobule, the liver’s hexagonal functional unit. Blood flows from the portal triad, located at the corners of the hexagon, towards a central vein in the middle. This creates distinct microenvironments along the path of blood flow.
The liver lobule is divided into three zones. Zone 1, the periportal zone, is closest to the portal triad, which supplies oxygen- and nutrient-rich blood. Zone 3, the pericentral zone, surrounds the central vein and receives blood lower in oxygen and nutrients. Zone 2, the mid-lobular zone, is situated between these regions. These varying concentrations of oxygen, nutrients, hormones, and signaling molecules create physiological gradients that drive the specialized activities of hepatocytes in each zone.
Metabolic Specialization by Zone
The gradients across the liver lobule lead to distinct metabolic roles for hepatocytes in each zone. Periportal hepatocytes (Zone 1) are exposed to higher oxygen and nutrient levels, making them suited for oxidative metabolic processes. These cells are involved in gluconeogenesis, the synthesis of glucose from non-carbohydrate sources, and fatty acid oxidation, which breaks down fats for energy. They also play a role in urea synthesis, detoxifying ammonia by converting it into urea.
As blood flows towards the pericentral zone (Zone 3), oxygen and nutrient concentrations decrease. Pericentral hepatocytes are involved in processes like glycolysis, the breakdown of glucose for energy, and lipogenesis, the synthesis of fats. These cells are also active in the detoxification of xenobiotics, foreign chemical substances like drugs and toxins, often through cytochrome P450 enzymes. Glutamine synthesis is largely confined to pericentral hepatocytes, while urea synthesis is restricted to periportal areas.
Maintaining Zonation
The establishment and maintenance of liver zonation involve various cellular and molecular mechanisms. Signaling pathways play a role in orchestrating differential gene expression across the lobule. The Wnt/β-catenin pathway is a regulator, with its activity highest in the pericentral zone. This pathway influences functions predominating in the pericentral zone, such as glutamine synthesis, drug metabolism, and bile acid synthesis. It also affects periportal functions like gluconeogenesis and urea synthesis.
Oxygen-sensing pathways, particularly those involving hypoxia-inducible factors (HIFs), are also involved. HIFs are active in pericentral regions where oxygen concentrations are lower. Other signaling molecules like growth factors and components of the Ras/MAPK/ERK pathway contribute to the patterning of gene expression. The continuous interplay of these pathways allows the liver to adapt its metabolic profile in response to changing conditions, such as fasting or feeding.
Clinical Relevance of Zonation
Understanding liver zonation has implications for health and disease. Disruptions in this spatial organization can contribute to various liver pathologies. For example, drug-induced liver injury often exhibits zone-specific damage, with some toxins preferentially affecting periportal or pericentral hepatocytes. This compartmentalization can limit initial damage to a specific zone, potentially allowing for regeneration from unaffected cells.
Zonation also influences metabolic diseases like non-alcoholic fatty liver disease (NAFLD), where abnormalities in glucose and fat metabolism can be spatially heterogeneous within the liver lobule. Knowledge of zonation is used for developing targeted therapies, as drug metabolism and toxicity can vary depending on the hepatocyte’s location. Studying zonation also helps researchers identify specific hepatocyte subpopulations responsible for regenerating damaged tissue.