The liver – microscopic structure of lobule

  • Liver lobules are the functional units of the liver consisting of groups of cells and vessels. Each lobule is made up of many hepatocytes (brown on illustration) which are the basic cells of the liver. Four types of vessels span the liver lobule. A central vein is in the centre of the lobule (blue in the illustration). On the edges of the lobules, there are so called portal triads that have three vessels: bile duct, portal vein and hepatic artery.

  • The bile duct (green in the illustration) transports bile to the gallbladder and the small intestine. The portal vein (blue in the illustration) carries blood from stomach, intestine, pancreas and speen into the liver. The hepatic artery (red in the illustration) transports blood reach in oxygen from the lungs to the liver.
  • Thus, the blood which enters the liver, enters it through the hepatic artery and portal vein on the corner of liver lobule. Then blood flows through the hepatocyte plates and finally drains into the central veins. From a metabolic perspective, the functional unit is the hepatic acinus (terminal acinus), each of which is centered on the line connecting two portal triads, and extends outwards to the two adjacent central veins.
  • The periportal zone I is nearest to the entering vascular supply and receives the most oxygenated blood. Conversely, the centrilobular zone III has the poorest oxygenation and is relatively more sensitive to ischemic injury.
  • Functionally, zone I hepatocytes are specialized on oxidative liver functions such as gluconeogenesis, β-oxidation of fatty acids and cholesterol synthesis, while zone III cells are more important for glycolysis, lipogenesis and cytochrome P-450-based drug detoxification. This specialization is reflected histologically; the detoxifying zone III cells have the highest concentration of CYP2E1 and thus are most sensitive to NAPQI production in acetaminophen toxicity. Other zonal injury patterns include zone I deposition of hemosiderin in hemochromatosis and zone II necrosis in yellow fever.

  • P.S. A term of liver lobule should not be confused with the anatomic lobes of the liver.
  • Authors: Martin Golebiewski and Iryna Ilkavets


    Image: Jill Zander and Iryna Ilkavets

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    Accumulated bile is transported in bile ductule

    The hepatocytes secrete bile salts, cholesterol and phospholipids into the bile fluid in the bile canaliculus. The bile salts of the bile fluid have an important function in the digestion of fats. Toxins and waste products are transported out of the body with the bile fluid as well. The bile is transported from the bile canaliculi into the bile ductule that runs parallel to the sinusoid.

  • While the blood flow is directed to the lobule center the bile flows horizontally from the center to the bile ducts that proceed vertically in the corners of the lobule hexagon together with the hepatic artery and the hepatic portal vein.
  • The bile from the different layers of the liver cells in the lobules accumulates in the bile ducts that are connected to the common bile duct through which the bile fluid is carried out of the liver organ.
  • Author: Johannes Eckstein
    Author of image: originally by Frevert U, Engelmann S, Zougbédé S, Stange J, Ng B, et al. Converted to SVG by Viacheslav Vtyurin who was hired to do so by User:Eug. Image was adapted by Johannes Eckstein
    Source of image: based on the research article [Intravital Observation of Plasmodium berghei Sporozoite Infection of the Liver, PLoS Biology](http://dx.doi.org/10.1371/journal.pbio.0030192).

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    Zonation of hepatic metabolism and its regulation

  • The liver is structured in small functional units called lobule. Within a lobule, nutrient-rich blood from the portal vein and oxygen-rich blood from the hepatic artery flow through small blood vessels, so-called sinusoids, to the central vein.

  • Hepatocytes along the sinusoid show differences in their cellular structure and enzyme activity. As a consequence, metabolic pathways are active in different zones along a sinusoid (functional zonation of hepatic metabolism).
  • Hepatocytes surrounding the portal triad belong to the periportal zone, whereas hepatocytes surrounding the central vein belong to the perivenous zone. Hepatocytes in these zones perform different metabolic activities.
  • The zonation of hepatic metabolism is the basis for the homeostasis of the organism. For example, opposite pathways, such as fatty acid degradation and fatty acid synthesis, can be spatially separated and, thus carried out simultaneously.
  • Most zonation patterns are flexible and dynamic; this means the metabolism and its zonal pattern adjust to the individual’s physiological state (e.g. nutritional conditions). This implies a well-regulated system. Here, an important regulator is oxygen availability. Because of the delivery of oxygen by arterial blood, cells in the periportal zone are exposed to a higher oxygen concentration than cells in the perivenous zone. Hepatocytes in the periportal zone take up oxygen from the blood and, therefore, decrease the blood oxygen concentration. In consequence, hepatocytes in the perivenous zone are subject to a lower oxygen supply.
  • Further factors influencing the zonation pattern of the metabolism are hormones (e.g. insulin, glucagon), nerve innervation, morphogens, and the circadian clock.
  • Author of text and image: Jana Schleicher

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    Polar hepatocytes communicate with other cells in a sinusoid

    Hepatocytes have a special membrane on some part of their cell “body”. This part of the membrane is non-sensitive to aggressive bile fluid and is called the apical membrane. When two hepatocytes face each other with these membranes, they form an intermediary space, in which bile fluid is secreted from hepatocytes.

    This space is called bile canaliculus.

  • On the image, the apical membrane of the hepatocytes is shown in green. The bile canaliculi contain bile. On the image bile is shown with green spheres.

  • The remainder of the hepatocyte membrane is the so-called basolateral membrane. With this membrane, the hepatocytes face (and communicate via the transport of metabolites) other cells in the sinusoid – hepatic stellate cells, sinusoidal endothelial cells and Kupffer cells.
  • Further reading
    Scientists achievements
    Author: Iryna Ilkavets
    Image: Jill Zander and Iryna Ilkavets

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    Zonation of the carbohydrate metabolism in the liver

  • The liver is structured in small functional units, which consist of small blood vessels, so-called sinusoids. They are surrounded by hepatocytes. There is a periportal region, where the blood enters the sinusoids coming from the hepatic artery and the portal vein, and a perivenous region, where the blood leaves the sinusoids and enters the central vein.

  • Along the sinusoids from periportal to perivenous the metabolic capacities of the individual hepatocytes vary and depend on the location within the sinusoid – the so-called zonation of the metabolism in the liver. Carbohydrates, besides lipids, are the main energy source of our body.
  • Hepatocytes in the periportal zone produce glucose via glycogenolysis and gluconeogenesis, whereas cells in the perivenous zone utilize glucose via glycogen synthesis and glycolysis. For this important task of continuous energy supply, the zonation of the carbohydrate metabolism can be an efficient solution, because synthesis and degradation can be spatially separated and a constant glucose level in the blood is obtained.
  • The gradients in oxygen, nutrients and hormonal signals like insulin and glucagon along the sinusoid play an important role for the carbohydrate metabolism and its zonation. Depending on the location of the hepatocytes within the sinusoid they encounter different environment and signals.
  • Authors: Matthias König and Jana Schleicher

  • Author of image: originally by Frevert U, Engelmann S, Zougbédé S, Stange J, Ng B, et al. Converted to SVG by Viacheslav Vtyurin who was hired to do so by User: Eug. Second Image (gradients): Matthias König

    Source of the first image: based on the research article Intravital Observation of Plasmodium berghei Sporozoite Infection of the Liver.

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    Zonation of the fat metabolism in the liver

  • Fat and carbohydrates are the main energy source of our body. To keep our body stable, a constant delivery of energy to the organs is necessary. This is a fine-tuned system of building-up and drawing down of storage pools (glycogen, triglycerides). The property of a system in which variables are regulated so that internal conditions remain stable and relatively constant is called homeostasis.

  • To perform the task of continuous energy delivery to the organs, a zonation of the fat and carbohydrate metabolism is an efficient solution. Hepatocytes in the periportal zone are part of an environment that is rich in oxygen and, after a meal, nutrients. Fatty acids are taken up from the blood streaming in from the portal vein (free fatty acids are highly toxic) and directed to oxidation, which provides the cell with energy. An excess of fatty acids overloads the oxidation pathway of periportal hepatocytes and further fatty acids are directed to the synthesis of non-toxic triglycerides.
  • Triglycerides are stored within the cells or exported via blood to adipose tissue. Triglyceride synthesis and storage occurs mainly in hepatocytes of the perivenous zone. The triglycerides in the liver cells and in adipose tissue serve as storage pools and can be reactivated in times of starvation. During fasting, when no fatty acids or carbohydrates are available from dietary intake, the triglyceride pools get activated (this means that fatty acids are released into blood from adipose tissue and triglycerides in the liver cells are converted to fatty acids) the liver cells use fatty acids for energy production (oxidation pathway) and the synthesis of ketone bodies.
  • Ketone bodies are produced from fatty acids and serve as energy source in times of carbohydrate shortage. Especially our brain relies on a constant supply of ketone bodies from the liver in fasting times, because fatty acids cannot pass the blood brain barrier, therefore cannot be used as energy source. Ketogenesis, the process of ketone body production, predominates in perivenous hepatocytes.
  • A diet that is high in carbohydrates leads to an up-regulation of fatty acid synthesis (production of fatty acids from glucose) a pathway that dominates in perivenous hepatocytes. This way, an excess of sugar is converted into an efficient storage form, triglycerides.
  • The zonation of the fat metabolism is very flexible and has a high potential of adaptation. For example, an excess of fatty acids in the blood can lead to the extension of triglyceride storage from the perivenous to the periportal zone. In this way, our body can react to varying food availability. How the zonation of fat metabolism is regulated is not well studied, but apparently oxygen supply through blood seems to play a major role.
  • Author: Jana Schleicher

  • Author of image: originally by Frevert U, Engelmann S, Zougbédé S, Stange J, Ng B, et al. Converted to SVG by Viacheslav Vtyurin who was hired to do so by User:Eug. Second Image (gradients): Christian Tokarski
    Source of the first image: based on the research article

    Intravital Observation of Plasmodium berghei Sporozoite Infection of the Liver.

  • Further reading: A theoretical study of lipid accumulation in the liver - implications for nonalcoholic fatty liver disease

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    Zonation of ammonia metabolism in the liver

  • Functional zonation plays an important role for ammonia detoxification. Ammonia is highly toxic and has to be removed from the blood. The blood streaming in from the portal vein and the hepatic artery delivers high ammonia, glutamine and other nitrogen-bearing compounds to hepatocytes in the periportal zone.

  • The hepatocytes take up glutamine and degrade it to additional ammonia and glutamate (by the activity of the enzyme glutaminase).
  • Some of the toxic ammonia is eliminated in urea synthesis (by the enzyme carbamoyl-phosphate synthetase). Glutamate and remaining ammonia are released by periportal hepatocytes and get absorbed by hepatocytes in the perivenous zone. In these cells, ammonia is converted back into glutamine (by glutamine synthetase (glutamate-ammonia ligase)), which can be released into the blood of the hepatic vein.
  • This way, the liver eliminates ammonia and prevents the delivery of toxic ammonia into the body’s blood circulation. In the early 1980s, it became obvious that urea and glutamine synthesis are almost completely separated. Recently, systems biology approaches (a combination of mathematical modeling and optimization techniques) showed that this spatial separation is optimal to fulfill the physiological tasks of the liver.
  • Authors: Martin Bartl, Sebastian Henkel and Jana Schleicher

  • Image: Sebastian Henkel

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