{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe NANP system plays a central role in maintaining blood glucose homeostasis by catalyzing the final, rate‐limiting step in both gluconeogenesis and glycogenolysis. In hepatocytes as well as other key tissues (including kidney, intestine, muscle, pancreatic islets, and even specialized brain cells such as astrocytes and tanycytes), NANP facilitates the hydrolysis of glucose‐6‐phosphate to free glucose and inorganic phosphate. This reaction is tightly controlled by hormonal and nutritional signals – for example, it is up‐regulated during fasting and under conditions of type 2 diabetes – and its transcription is modulated by diverse nuclear receptors and transcriptional co‐activators (such as PGC‐1α, NF‐Y, and SRC‐2) and is subject to regulation by factors including cAMP, glucagon, and insulin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn pathological contexts, loss of or mutations within the NANP system lead to severe metabolic derangements. Deficiencies are associated with glycogen storage diseases that manifest as fasting hypoglycemia, abnormal glycogen and lipid accumulation, and in some cases, progression to hepatocellular adenomas or carcinomas. These metabolic perturbations are compounded by alterations in cellular bioenergetics – including impaired mitochondrial oxidative phosphorylation, increased glycolytic flux and hexose monophosphate shunt activity, and disrupted autophagy. Furthermore, novel therapeutic strategies, from gene therapy using viral vectors and CRISPR‐mediated genome editing to shRNA knockdown approaches, have demonstrated the potential for restoring NANP function and improving metabolic outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the liver, the NANP system is operative in other tissues where it contributes to local and systemic energy regulation. For example, its expression in pancreatic islets suggests a role in modulating insulin secretion, while in the brain and hypothalamic structures (and via vesicular pathways potentially linked to Caveolin‐1–mediated cholesterol trafficking) it is implicated in central energy balance. Moreover, interactions with accessory enzymes – such as hexose‑6‑phosphate dehydrogenase and 11β‑hydroxysteroid dehydrogenase type 1 – highlight its integration into broader glucocorticoid and metabolic signaling networks, thereby ensuring coordinated regulation across multiple organ systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jared N Boustead, Beth T Stadelmaier, Angela M Eeds, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte nuclear factor-4 alpha mediates the stimulatory effect of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20021382"}], "href": "https://doi.org/10.1042/BJ20021382"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12416993"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12416993"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Bee-Hoon Goh, Suad Efendić, Akhtar Khan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence for the expression of both the hydrolase and translocase components of hepatic glucose-6-phosphatase in murine pancreatic islets."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0006-291x(03)01242-7"}], "href": "https://doi.org/10.1016/s0006-291x(03"}, {"type": "t", "text": "01242-7) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12878201"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12878201"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Li-Yuan Chen, Jeng-Jer Shieh, Baochuan Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddg263"}], "href": "https://doi.org/10.1093/hmg/ddg263"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12925567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12925567"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Alan Huang, Yan Chen, Xinzhong Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional silencing of hepatic microsomal glucose-6-phosphatase gene expression in vivo by adenovirus-mediated delivery of short hairpin RNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0014-5793(03)01499-6"}], "href": "https://doi.org/10.1016/S0014-5793(03"}, {"type": "t", "text": "01499-6) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14759518"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14759518"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jeng-Jer Shieh, Chi-Jiunn Pan, Brian C Mansfield, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A potential new role for muscle in blood glucose homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M402036200"}], "href": "https://doi.org/10.1074/jbc.M402036200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15087461"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15087461"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Abhijit Ghosh, Yuk Yin Cheung, Brian C Mansfield, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Brain contains a functional glucose-6-phosphatase complex capable of endogenous glucose production."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M410894200"}], "href": "https://doi.org/10.1074/jbc.M410894200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15661744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15661744"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sang-Ki Park, Volker H Haase, Randall S Johnson "}, {"type": "b", "children": [{"type": "t", "text": "von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17203215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17203215"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Keiko Hirota, Jun-ichi Sakamaki, Junji Ishida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M806179200"}], "href": "https://doi.org/10.1074/jbc.M806179200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18805788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18805788"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hiroshi Onuma, James K Oeser, Bryce A Nelson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insulin and epidermal growth factor suppress basal glucose-6-phosphatase catalytic subunit gene transcription through overlapping but distinct mechanisms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20080999"}], "href": "https://doi.org/10.1042/BJ20080999"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18847435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18847435"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Atul R Chopra, Jean-Francois Louet, Pradip Saha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1164847"}], "href": "https://doi.org/10.1126/science.1164847"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19039140"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19039140"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Seung-Soon Im, Mi-Young Kim, Sool-Ki Kwon, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peroxisome proliferator-activated receptor {alpha} is responsible for the up-regulation of hepatic glucose-6-phosphatase gene expression in fasting and db/db Mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.157875"}], "href": "https://doi.org/10.1074/jbc.M110.157875"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21081500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21081500"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Elodie Mutel, Amandine Gautier-Stein, Aya Abdul-Wahed, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db11-0571"}], "href": "https://doi.org/10.2337/db11-0571"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22013018"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22013018"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Mirit Eynan, Dimitry Tsitlovsky, Liron Batit, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Is glucose-6-phosphate dehydrogenase deficiency a risk factor for hyperbaric oxygen exposure?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Appl Physiol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00421-011-2229-0"}], "href": "https://doi.org/10.1007/s00421-011-2229-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22075642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22075642"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Christine Bernsmeier, Michael T Dill, Angela Provenzano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatic Notch1 deletion predisposes to diabetes and steatosis via glucose-6-phosphatase and perilipin-5 upregulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lab Invest (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/labinvest.2016.75"}], "href": "https://doi.org/10.1038/labinvest.2016.75"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27428080"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27428080"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Benjamin L Farah, Rohit A Sinha, Yajun Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatic mitochondrial dysfunction is a feature of Glycogen Storage Disease Type Ia (GSDIa)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep44408"}], "href": "https://doi.org/10.1038/srep44408"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28317891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28317891"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Agnieszka E Zielinska, Rachel S Fletcher, Mark Sherlock, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cellular and genetic models of H6PDH and 11β-HSD1 function in skeletal muscle."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Funct (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbf.3272"}], "href": "https://doi.org/10.1002/cbf.3272"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28749080"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28749080"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yanjie Zhang, Qiuyue Guan, Yin Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of hepatic gluconeogenesis by nuclear factor Y transcription factor in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA117.000508"}], "href": "https://doi.org/10.1074/jbc.RA117.000508"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29530977"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29530977"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Jun-Ho Cho, Goo-Young Kim, Brian C Mansfield, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2018.03.083"}], "href": "https://doi.org/10.1016/j.bbrc.2018.03.083"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29545180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29545180"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Fabienne Rajas, Renaud Dentin, Alexane Cannella Miliano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The absence of hepatic glucose-6 phosphatase/ChREBP couple is incompatible with survival in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Metab (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molmet.2020.101108"}], "href": "https://doi.org/10.1016/j.molmet.2020.101108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33137488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33137488"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Irina Arnaoutova, Lisa Zhang, Hung-Dar Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Correction of metabolic abnormalities in a mouse model of glycogen storage disease type Ia by CRISPR/Cas9-based gene editing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Ther (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymthe.2020.12.027"}], "href": "https://doi.org/10.1016/j.ymthe.2020.12.027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33359667"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33359667"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Anouk M La Rose, Venetia Bazioti, Joanne A Hoogerland, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatocyte-specific glucose-6-phosphatase deficiency disturbs platelet aggregation and decreases blood monocytes upon fasting-induced hypoglycemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Metab (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molmet.2021.101265"}], "href": "https://doi.org/10.1016/j.molmet.2021.101265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34091064"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34091064"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Amandine Gautier-Stein, Julien Chilloux, Maud Soty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A caveolin-1 dependent glucose-6-phosphatase trafficking contributes to hepatic glucose production."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Metab (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molmet.2023.101700"}], "href": "https://doi.org/10.1016/j.molmet.2023.101700"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36870604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36870604"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Emily M Hawes, Kayla A Boortz, James K Oeser, et al. "}, {"type": "b", "children": [{"type": "t", "text": "G6PC1 and G6PC2 influence G6P flux but not HSD11B1 activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Endocrinol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1530/JME-23-0070"}], "href": "https://doi.org/10.1530/JME-23-0070"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37855366"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37855366"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "María José Barahona, Luciano Ferrada, Matías Vera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tanycytes release glucose using the glucose-6-phosphatase system during hypoglycemia to control hypothalamic energy balance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Metab (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molmet.2024.101940"}], "href": "https://doi.org/10.1016/j.molmet.2024.101940"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38641253"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38641253"}]}]}]}