The liver comprises different cells

  • Two major types of cells populate the liver lobes: parenchymal and non-parenchymal cells. 80% of the liver volume is occupied by parenchymal cells commonly referred to as hepatocytes. Non-parenchymal cells constitute 40% of the total number of liver cells but only 6.5% of its volume.

  • Sinusoidal endothelial cells, Kupffer cells and hepatic stellate cells are some of the non-parenchymal cells that line the hepatic sinusoid. Hepatocytes, the most abundant cell type of the liver, exist in a 3D arrangement as plates or sheets organized along hepatic sinusoids. Thereby, distinct apical (towards bile canaliculi) and basolateral (towards the blood) domains are established for each hepatocyte.
  • Hepatocytes are the cells, which carry out the fundamental metabolic processes of the liver. These comprise glucostat function, storage of carbohydrates, ammonia metabolism, detoxification, xenobiotic metabolism and synthesis of lipids, triglycerides, cholesterol, bile salts, bile and phospholipids. Furthermore, hepatocytes are the major source of plasma protein and lipoprotein synthesis.

  • In order to perform these diverse functions simultaneously, hepatocytes show a remarkable heterogeneity along the sinusoids. The observed metabolic zonation results from complex interactions of gradients of nutrients and hormones (Gebhardt, 1992; Häussinger and Schliess, 2007), and, according to recent results, is controlled by morphogens acting as master regulators (Benhamouche et al., 2006; Gebhardt and Hovhannisyan, 2009).
  • Author: Martin Golebiewski

  • 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.

    Source of image: Intravital Observation of Plasmodium berghei Sporozoite Infection of the Liver, PLoS Biology.

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    Liver cells secrete bile

    Between neighboring hepatocytes a bile canaliculus can form. The canalicular membrane facing the bile canaliculus is separated by barriers called tight junctions from the rest of the cell membrane facing other cells and the blood (basolateral membrane).

  • The canalicular membrane consists of proteins and lipids that are different as those in the basolateral membrane. It has proteins that are able to pump bile salts into the bile canaliculus (BSEP) and proteins that pump lipids from the inner to the outer side of the membrane (MDR3).
  • The bile salts (BS) dissolve lipids (CH: cholesterol, PC: phosphatidylcholine, SM: sphingomyelin) from the membrane into the bile fluid inside the bile canaliculus where they form mixed micelles. With the pumping proteins BSEP and MDR3 the cell is able to control the bile salt concentration and the lipid content of the bile fluid.
  • Author: Johannes Eckstein

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    Syntaxin 3 and Syntaxin 4 proteins determine polarity of hepatocytes

    Hepatocytes are the most prominent cells of the liver tissue. A hepatocyte is surrounded by a so-called polar plasma membrane, which is splitted into two different sections (domains) with separate tasks to fulfill. The smaller apical membrane domains form bile canaliculi with neighboring hepatocytes.

  • The bile canaliculi are thin tubes that collect bile secreted by hepatocytes. In contrast to the apical membrane sections, the basolateral sections adjoin the so-called liver sinusoids and are therefore responsible for the exchange of metabolites and proteins with the blood.

  • Apical and basolateral membrane domains of a hepatocyte are equipped with different proteins according to their different tasks. For example, syntaxin 3 proteins are predominantly found at the apical and syntaxin 4 at the basolateral membrane domain. The particular feature of these two proteins is that they segregate into larger clusters before the hepatocyte membrane is fully polarized e.g. during the de novo formation of the cell.
  • Scientists investigated these processes and found that those clusters represent a preliminary polarity of the membrane.
  • Author: Bernd Binder

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    The liver is a main storage of glucose

    Glucose production and glucose utilization are a result of the metabolism in the liver. The hepatic metabolism is the set of chemical transformations within the hepatocytes, the main cell type of the liver. Hepatocytes play a central role in the glucose metabolism:

  • 1) they are able to store glucose in its storage form glycogen when blood glucose levels are high, a process called glycogen synthesis;
  • 2) they release glucose from glycogen when the glucose level is low (glycogenolysis);
  • 3) they can use glucose to produce energy when the glucose level is high by initiating a set of chemical conversions called glycolysis;
  • 4) under low-glucose level conditions, they can also produce glucose from precursors in a process called gluconeogenesis or de novo glucose synthesis.
  • These bio-transformations of glucose are conducted by enzymes, small specialized molecular machines within the hepatocytes, which can be modified in their activity as a consequence of changing levels of the hormone signals insulin and glucagon.
  • Creative Commons License
    VLN glucose metabolism by Matthias Koenig is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 nternational License.
    Based on a work at http://www.charite.de/sysbio/people/koenig/

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    Hepatocytes sense and react to hepatocyte growth factor

    Hepatocyte growth factor (HGF) is a protein. The major function of HGF is to motivate hepatocytes to divide (proliferate). Therefore HGF is recognized as a mitogen. As shown on image (portrait of HGF), HGF has a complex structure.

  • However, such a structure is typical for many proteins. While approaching the hepatocyte, a molecule of HGF is sensed by hepatocyte. Then HGF binds (connects) to its receptor on the hepatocyte. The receptor is called c-Met. Upon HGF binding, c-Met transmits the action of HGF from outside to inside of hepatocytes. This action of HGF regulates cell growth, cell motility, and morphogenesis.
  • Authors: Martin Golebiewski and Iryna Ilkavets

  • Image from Wikipedia, author Emw

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    The lipid droplets serve as energy storage depots

    Lipids enter the cells as free fatty acids or free cholesterol. These lipids can also be produced (synthesized) by the hepatocyte itself. However, high concentrations of free fatty acids and cholesterol can damage cells.

    Therefore, they are converted by hepatocytes (biotransformed or detoxified) into non-toxic neutral lipids, e.g. diacylglycerols and triacylglycerids. During this conversion, free fatty acids and cholesterol are coesterified.

  • "New" neutral lipids can form lipid droplets (which also contain the remainder of free fatty acids, cholesterols, and also phospholipids).
  • The lipid droplets serve as energy storage for later use in the hepatocyte. They can move within the hepatocyte, skate around on the cytoskeleton, and physically interact with organelles. Lipid droplets can also “escape” the hepatocyte: droplets migrate to the sinusoidal membrane of the hepatocyte, fuse with the membrane and are released into the blood in the form of lipoproteins.
  • Author of text and image: Iryna Ilkavets

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    Endocytosis delivers cargo into the cell to endosomes

    Liver cells (hepatocytes) constantly absorb and release nutrients and receive and process signals in order to fulfill the liver functions. To carry out these processes, the cell has a dynamic network of hundreds of small organelles known as endosomes that play a central role in distributing the internalized substances and in transmitting the signals.

  • Signaling molecules and receptors are absorbed by the cell by invagination of the cell surface: a process called endocytosis. Following that, the cargo is sequestered into small transport vesicles that fuse with early endosomes.
  • Early endosomes are specialized endosomes that function as sorting stations in the cell. Once delivered to early endosomes, these vesicles travel to different cellular compartments to distribute their cargo to their correct destination. Some cargo such as receptors or transporters is recycled back to the cell surface via the recycling endosome for another round of internalization. Alternatively, other cargo molecules are routed to the digestive center of the cell, the lysosome, where they are degraded.
  • The image shows the endosomal transport in liver cells. Vesicles containing internalized cargo are transported to early endosomes for further sorting: The cargo is either recycled back to the cell surface through recycling endosomes or is alternatively transported via late endosomes to the lysosomes, to be degraded.
  • In order to understand the important contributions of endosomes for liver cell physiology and pathology, scientists interfered with this sorting station and unraveled novel function of endosomes beyond cellular transport.
  • Authors of text and image: Anja Zeigerer and Marino Zerial

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    The dynamics of biochemical processes – a task for ordinary differential equations

    Mathematically simulating the dynamics of a biochemical network can lead to a better understanding of the involved biochemical processes. The simulated networks, also called ODE models, consist of biochemical components (often referred to as metabolites). These components are connected by reactions transforming the metabolites into each other. In contrast to general stoichiometric models the reaction dynamics are known.

  • During a dynamic model simulation the velocities of all reactions are calculated repeatedly and the concentrations of the metabolites are always updated. Usually, the velocity of a reaction depends directly on the current concentrations of the metabolites taking part in it. This dependency is described by ordinary differential equations (ODEs) The ODEs represent the dynamics of the simulation, but it is also necessary to know where to start a simulation. Therefore, the initial concentrations of all metabolites are necessary to be known. Based on the ODEs and the initial concentrations, mathematical methods can determine the concentrations from the initial time point up to a desired end time.
  • While the initial concentrations for the start of the simulation are often experimentally measured, the ODEs of the reactions, also called reaction kinetics, are harder to obtain. One possibility is to take the information about reaction kinetics from publications. But there are also dedicated databases like SABIO-RK enabling to search for kinetics of specific reactions.
  • ODE models are only useful, if they can explain cellular processes. In order to demonstrate this, a model is simulated and the simulation results are compared to adequate time-resolved experimental data. Apart from that, experimental data are often used for adaptation of unknown parameters contained in reaction kinetics. Thereby those parameters are repeatedly set to different values and simulations are conducted based on those values. Then for each simulation the distance between simulation results and experimental data is calculated. Mathematical routines help to improve the parameter values.
  • Author: Roland Keller

  • Image: Stephanie Hoffmann

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