Liver zonation

View Large Image Figure ViewerDownload Hi-res image Download (PPT) The liver is a central organ that preserves physiological homeostasis. It is a highly structured organ composed of hexagonal-shaped anatomical units termed ‘liver lobules’. Blood rich in oxygen enters the liver lobule at peripheral portal tracts and drains out through the central vein. Conversely, bile flows outwards from the lobule centres and drains out through portal bile ducts.[1]Godoy P. Hewitt N.J. Albrecht U. Andersen M.E. Ansari N. Bhattacharya S. et al.Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.Arch Toxicol. 2013; 87: 1315-1530Crossref PubMed Scopus (838) Google Scholar Hepatocytes, the main liver cell type, are arranged in hepatic plates that extend radially along the lobule axis. At the basolateral domains, hepatocytes face fenestrated endothelial cells that form the radial sinusoidal blood vessels. Hepatic stellate cells (HSCs), vitamin A storing cells that can become extracellular matrix producers, reside in the “space of Disse” between hepatocytes and the sinusoids. Kupffer cells (KCs), the liver resident macrophages, are largely immotile cells residing within the sinusoids. As blood flows inwards, hepatocytes take up and secrete nutrients and sense hormones (insulin, glucagon, growth and thyroid hormones). Sequential hepatocyte consumption and production, together with local tissue morphogens, give rise to a graded microenvironment. In line with these gradients, liver functions are non-uniformly distributed along the lobule radial axis, a phenomenon that has been termed “liver zonation”.[2]Jungermann K. Keitzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver.Annu Rev Nutr. 1996; 16: 179-203Crossref PubMed Scopus (396) Google Scholar,[11]Diamantis I. Boumpas D.T. Autoimmune hepatitis: evolving concepts.Autoimmun Rev. 2004; 3: 207-214Crossref PubMed Scopus (38) Google Scholar Hepatocyte zonation patterns seem to optimize overall liver function, in the face of structural constraints.[3]Gebhardt R. Matz-Soja M. Liver zonation: novel aspects of its regulation and its impact on homeostasis.World J Gastroenterol. 2014; 20: 8491-8504Crossref PubMed Scopus (156) Google Scholar Processes that are energetically demanding, such as protein secretion and gluconeogenesis, are allocated to the portal layers, where oxygen is more abundant. Mid-lobule hepatocytes specialize in the secretion of the iron-regulating hormone hepcidin, among other tasks. Pericentral hepatocytes preferentially engage in xenobiotic metabolism, bile acid biosynthesis and glycolysis, which are less energetically demanding processes.[3]Gebhardt R. Matz-Soja M. Liver zonation: novel aspects of its regulation and its impact on homeostasis.World J Gastroenterol. 2014; 20: 8491-8504Crossref PubMed Scopus (156) Google Scholar,[4]Halpern K.B. Shenhav R. Matcovitch-Natan O. Tóth B. Lemze D. Golan M. et al.Single-cell spatial reconstruction reveals global division of labour in the mammalian liver.Nature. 2017; 542: 352-356Crossref PubMed Scopus (399) Google Scholar Some zonated processes exhibit spatial recycling of material. An example is the urea cycle, where periportal hepatocytes detoxify ammonia to generate urea, a task that requires the breakdown of glutamine into glutamate.[1]Godoy P. Hewitt N.J. Albrecht U. Andersen M.E. Ansari N. Bhattacharya S. et al.Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.Arch Toxicol. 2013; 87: 1315-1530Crossref PubMed Scopus (838) Google Scholar Pericentral hepatocytes, in turn, take up the excess glutamate and reconvert it to glutamine, thus maintaining amino acid balance at the entries and exits of the lobule. Additional examples of opposite zonated tasks include periportal production and pericentral uptake of glucose, as well as periportal cholesterol biosynthesis and pericentral cholesterol consumption. Some pathways, such as the neutral bile acid biosynthesis cascade, follow ‘production line’ patterns, whereby sequential enzymes in the cascade are expressed in sequential lobule layers.[3]Gebhardt R. Matz-Soja M. Liver zonation: novel aspects of its regulation and its impact on homeostasis.World J Gastroenterol. 2014; 20: 8491-8504Crossref PubMed Scopus (156) Google Scholar,[4]Halpern K.B. Shenhav R. Matcovitch-Natan O. Tóth B. Lemze D. Golan M. et al.Single-cell spatial reconstruction reveals global division of labour in the mammalian liver.Nature. 2017; 542: 352-356Crossref PubMed Scopus (399) Google Scholar Of note, there are discrepancies between human and mouse zonation.[5]Ben-Moshe S. Itzkovitz S. Spatial heterogeneity in the mammalian liver.Nat Rev Gastroenterol Hepatol. 2018; 16: 395-410Crossref Scopus (88) Google Scholar The Wnt pathway stands out as a major regulator of hepatic zonation, as about a third of hepatic zonated genes are Wnt targets.[11]Diamantis I. Boumpas D.T. Autoimmune hepatitis: evolving concepts.Autoimmun Rev. 2004; 3: 207-214Crossref PubMed Scopus (38) Google Scholar The pericentral liver endothelial cells are a source of key Wnt-pathway ligands such as Wnt2, Wnt9b and Rspo3,[6]Aizarani N. Saviano A. Sagar Mailly L. Durand S. Herman J.S. et al.A human liver cell atlas reveals heterogeneity and epithelial progenitors.Nature. 2019; 572: 199-204Crossref PubMed Scopus (313) Google Scholar the latter also expressed by pericentral HSCs.[8]Dobie R. Wilson-Kanamori J.R. Henderson B.E.P. Smith J.R. Matchett K.P. Portman J.R. et al.Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis.Cell Rep. 2019; 29: 1832-1847.e8Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Pericentral HSCs further express elevated levels of Sox4 and Adamtsl2, whereas periportal HSCs exhibit zonated expression of Ngfr, Il34 and Tagln.[8]Dobie R. Wilson-Kanamori J.R. Henderson B.E.P. Smith J.R. Matchett K.P. Portman J.R. et al.Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis.Cell Rep. 2019; 29: 1832-1847.e8Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Periportal KCs are more abundant, larger and exhibit higher phagocytic activity compared to pericentral KCs.[9]Vollmar B. Menger M.D. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair.Physiol Rev. 2009; 89: 1269-1339Crossref PubMed Scopus (333) Google Scholar Periportal KCs produce more Tnfα and Pge2, while pericentral KCs produce more Il-1.[9]Vollmar B. Menger M.D. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair.Physiol Rev. 2009; 89: 1269-1339Crossref PubMed Scopus (333) Google Scholar Liver zonation can explain zonated damage in liver pathology. The zonated processes of xenobiotic metabolism lead to pericentral damage upon overdoses of drugs such as acetaminophen. This is due to the accumulation of toxic intermediates exclusively in the hepatocytes that express the detoxification machinery, especially Cyp2e1 and Cyp1a2.[10]Anundi I. Lähteenmäki T. Rundgren M. Moldeus P. Lindros K.O. Zonation of acetaminophen metabolism and cytochrome P450 2E1-mediated toxicity studied in isolated periportal and perivenous hepatocytes.Biochem Pharmacol. 1993; 45: 1251-1259Crossref PubMed Scopus (87) Google Scholar Pericentral injury is also associated with the activation of pericentral HSCs.[7]Halpern K.B. Shenhav R. Massalha H. Toth B. Egozi A. Massasa E.E. et al.Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells.Nat Biotechnol. 2018; 36: 962-970Crossref PubMed Scopus (128) Google Scholar The development of non-alcoholic and alcohol-related liver diseases mostly begins in the pericentral zone as well, potentially linked to its higher lipogenic activity.[4]Halpern K.B. Shenhav R. Matcovitch-Natan O. Tóth B. Lemze D. Golan M. et al.Single-cell spatial reconstruction reveals global division of labour in the mammalian liver.Nature. 2017; 542: 352-356Crossref PubMed Scopus (399) Google Scholar Periportal damage is observed in autoimmune hepatitis, in part due to the zonated expression of antigens such as CD54 and CD58,[10]Anundi I. Lähteenmäki T. Rundgren M. Moldeus P. Lindros K.O. Zonation of acetaminophen metabolism and cytochrome P450 2E1-mediated toxicity studied in isolated periportal and perivenous hepatocytes.Biochem Pharmacol. 1993; 45: 1251-1259Crossref PubMed Scopus (87) Google Scholar and in biliary diseases, due to the damage to epithelial cells that form the periportal bile duct.[4]Halpern K.B. Shenhav R. Matcovitch-Natan O. Tóth B. Lemze D. Golan M. et al.Single-cell spatial reconstruction reveals global division of labour in the mammalian liver.Nature. 2017; 542: 352-356Crossref PubMed Scopus (399) Google Scholar S.I. is supported by the Wolfson Family Charitable Trust, the Edmond de Rothschild Foundations, the Fannie Sherr Fund, the Helen and Martin Kimmel Institute for Stem Cell Research grant, the Minerva grant, the Israel Science Foundation grant No. 1486/16, the Broad Institute-Israel Science Foundation grant No. 2615/18, the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant No. 335122, the Chan Zuckerberg Initiative grant No. CZF2019-002434, the Bert L. and N. Kuggie Vallee Foundation and the Howard Hughes Medical Institute (HHMI) international research scholar award. Both authors wrote the paper. Data are available online. The authors declare no competing personal or financial interests. 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