Ben-Moshe, S. & Itzkovitz, S. Spatial heterogeneity in the mammalian liver. Nat. Rev. Gastroenterol. Hepatol. 16, 395–410 (2019).
Kang, J. et al. Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis. Proc. Natl Acad. Sci. USA 112, E4236–E4245 (2015).
Kim, S. G. et al. Bilirubin activates transcription of HIF-1α in human proximal tubular cells cultured in the physiologic oxygen content. J. Kor. Med. Sci. 29, S146–S154 (2014).
Martini, T., Naef, F. & Tchorz, J. S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu. Rev. Pathol. Mech. Dis. 18, 439–466 (2023).
Bartl, M. et al. Optimality in the zonation of ammonia detoxification in rodent liver. Arch. Toxicol. 89, 2069–2078 (2015).
Husson, A., Brasse-Lagnel, C., Fairand, A., Renouf, S. & Lavoinne, A. Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle. Eur. J. Biochem. 270, 1887–1899 (2003).
Häussinger, D. Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem. J 267, 281–290 (1990).
van Straten, G. et al. Aberrant expression and distribution of enzymes of the urea cycle and other ammonia metabolizing pathways in dogs with congenital portosystemic shunts. PLoS ONE 9, e100077 (2014).
McNaughton, L. et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proc. Natl Acad. Sci. USA 99, 17161–17166 (2002).
Baldelli, S. et al. Glutathione and nitric oxide: key team players in use and disuse of skeletal muscle. Nutrients 11, 2318 (2019).
Yu, Y. et al. A comparative analysis of liver transcriptome suggests divergent liver function among human, mouse and rat. Genomics 96, 281–289 (2010).
Jiang, C. et al. Comparative transcriptomics analyses in livers of mice, humans, and humanized mice define human-specific gene networks. Cells 9, 2566 (2020).
Cunningham, R. P. & Porat-Shliom, N. Liver zonation—revisiting old questions with new technologies. Front. Physiol. 12, 732929 (2021).
Kolbe, E. et al. Mutual zonated interactions of Wnt and Hh signaling are orchestrating the metabolism of the adult liver in mice and human. Cell Rep. 29, 4553–4567.e4557 (2019).
Wahlicht, T. et al. Controlled functional zonation of hepatocytes in vitro by engineering of Wnt signaling. ACS Synth. Biol. 9, 1638–1649 (2020).
Nejak-Bowen, K. N., Zeng, G., Tan, X., Cieply, B. & Monga, S. P. Beta-catenin regulates vitamin C biosynthesis and cell survival in murine liver. J. Biol. Chem. 284, 28115–28127 (2009).
Bacchus, H., Heiffer, M. H. & Altszuler, N. Potentiating effect of ascorbic acid on cortisone-induced gluconeogenesis. Proc. Soc. Exp. Biol. Med. 79, 648–650 (1952).
Greene, Y. J., Harwood, H. J. & Stacpoole, P. W. Ascorbic acid regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol synthesis in guinea pig liver. Biochim. Biophys. Acta 834, 134–138 (1985).
Creeden, J. F., Gordon, D. M., Stec, D. E. & Hinds, T. D. Jr. Bilirubin as a metabolic hormone: the physiological relevance of low levels. Am. J. Physiol. Endocrinol. Metab. 320, E191–E207 (2021).
Gazzin, S. et al. Bilirubin accumulation and Cyp mRNA expression in selected brain regions of jaundiced Gunn rat pups. Pediatr. Res. 71, 653–660 (2012).
Tanii, H. et al. Induction of cytochrome P450 2A6 by bilirubin in human hepatocytes. Pharmacol. Pharm. 4, 182–190 (2013).
Ma, R., Martínez-Ramírez, A. S., Borders, T. L., Gao, F. & Sosa-Pineda, B. Metabolic and non-metabolic liver zonation is established non-synchronously and requires sinusoidal Wnts. eLife 9, e46206 (2020).
Cui, J., Pan, Y. H., Zhang, Y., Jones, G. & Zhang, S. Progressive pseudogenization: vitamin C synthesis and its loss in bats. Mol. Biol. Evol. 28, 1025–1031 (2011).
Reza, H. A. et al. Synthetic augmentation of bilirubin metabolism in human pluripotent stem cell-derived liver organoids. Stem Cell Rep. 18, 2071–2083 (2023).
Horio, F., Ozaki, K., Yoshida, A., Makino, S. & Hayashi, Y. Requirement for ascorbic acid in a rat mutant unable to synthesize ascorbic acid. J. Nutr. 115, 1630–1640 (1985).
Kimura, M. et al. En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH. Cell 185, 4216–4232.e4216 (2022).
Ouchi, R. et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab. 30, 374–384.e376 (2019).
Shinozawa, T. et al. High-fidelity drug-induced liver injury screen using human pluripotent stem cell-derived organoids. Gastroenterology 160, 831–846.e810 (2021).
McCarty, W. J., Usta, O. B. & Yarmush, M. L. A microfabricated platform for generating physiologically-relevant hepatocyte zonation. Sci. Rep. 6, 26868 (2016).
Andrews, T. S. et al. Single-cell, single-nucleus, and spatial rna sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity. Hepatol. Commun. 6, 821–840 (2022).
Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).
MacParland, S. A. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 (2018).
Wesley, B. T. et al. Single-cell atlas of human liver development reveals pathways directing hepatic cell fates. Nat. Cell Biol. 24, 1487–1498 (2022).
Camp, J. G. et al. Multilineage communication regulates human liver bud development from pluripotency. Nature 546, 533–538 (2017).
Guan, Y. et al. A human multi-lineage hepatic organoid model for liver fibrosis. Nat. Commun. 12, 6138 (2021).
Harrison, S. P. et al. Scalable production of tissue-like vascularized liver organoids from human PSCs. Exp. Mol. Med. 55, 2005–2024 (2023).
Hess, A. et al. Single‐cell transcriptomics stratifies organoid models of metabolic dysfunction‐associated steatotic liver disease. EMBO J. 42, e113898 (2023).
Zhang, C. J. et al. A human liver organoid screening platform for DILI risk prediction. J. Hepatol. 78, 998–1006 (2023).
Dann, E., Henderson, N. C., Teichmann, S. A., Morgan, M. D. & Marioni, J. C. Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat. Biotechnol. 40, 245–253 (2022).
Ton, M.-L. N. et al. An atlas of rabbit development as a model for single-cell comparative genomics. Nat. Cell Biol. 25, 1061–1072 (2023).
Thakur, A. et al. Hepatocyte nuclear factor 4-alpha is essential for the active epigenetic state at enhancers in mouse liver. Hepatology 70, 1360–1376 (2019).
Raisner, R. et al. Enhancer activity requires CBP/P300 bromodomain-dependent histone H3K27 acetylation. Cell Rep. 24, 1722–1729 (2018).
Smith, R. P. et al. Genome-wide discovery of drug-dependent human liver regulatory elements. PLoS Genet. 10, e1004648 (2014).
Ölander, M. et al. Hepatocyte size fractionation allows dissection of human liver zonation. J. Cell. Physiol. 236, 5885–5894 (2021).
Kang, S. W. S. et al. A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling. Nat. Commun. 15, 1799 (2024).
Mariotti, V., Strazzabosco, M., Fabris, L. & Calvisi, D. F. Animal models of biliary injury and altered bile acid metabolism. Biochim. Biophys. Acta 1864, 1254–1261 (2018).
Claeys, W. et al. A mouse model of hepatic encephalopathy: bile duct ligation induces brain ammonia overload, glial cell activation and neuroinflammation. Sci. Rep. 12, 17558 (2022).
Goto, Y., Ohashi, K., Utoh, R., Yamamoto, M. & Okano, T. Hepatocyte transplantation through the hepatic vein: a new route of cell transplantation to the liver. Cell Transplant. 20, 1259–1270 (2011).
Paris, J. & Henderson, N. C. Liver zonation, revisited. Hepatology 76, 1219–1230 (2022).
Scheidecker, B. et al. Induction of in vitro metabolic zonation in primary hepatocytes requires both near-physiological oxygen concentration and flux. Front. Bioeng. Biotechnol. 8, 524 (2020).
Bartl, M. et al. Model-based optimization to explain liver zonation in nitrogen metabolism. In 55th International Scientific Colloquium 235–240 (TU Ilmenau, 2021).
Harrison, S. P. et al. Liver organoids: recent developments, limitations and potential. Front. Med. https://doi.org/10.3389/fmed.2021.574047 (2021).
Wei, Y. et al. Liver homeostasis is maintained by midlobular zone 2 hepatocytes. Science 371, eabb1625 (2021).
He, L. et al. Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair. Science 371, eabc4346 (2021).
Li, W., Li, L. & Hui, L. Cell plasticity in liver regeneration. Trends Cell Biol. 30, 329–338 (2020).
Brosch, M. et al. Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nat. Commun. 9, 4150 (2018).
Xu, W. et al. Hypoxia activates Wnt/β-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma. Sci. Rep. 7, 40446 (2017).
Kietzmann, T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol. 11, 622–630 (2017).
Iansante, V., Mitry, R. R., Filippi, C., Fitzpatrick, E. & Dhawan, A. Human hepatocyte transplantation for liver disease: current status and future perspectives. Pediatr. Res. 83, 232–240 (2018).
Reza, H. A., Okabe, R. & Takebe, T. Organoid transplant approaches for the liver. Transpl. Int. 34, 2031–2045 (2021).
Wu, H., Kirita, Y., Donnelly, E. L. & Humphreys, B. D. Advantages of single-nucleus over single-cell RNA sequencing of adult kidney: rare cell types and novel cell states revealed in fibrosis. J. Am. Soc. Nephrol. 30, 23–32 (2019).
He, L. et al. Transcriptional co-activator p300 maintains basal hepatic gluconeogenesis. J. Biol. Chem. 287, 32069–32077 (2012).
