{"entity": "researcher", "timestamp": "2026-08-15T13:38:43.376Z", "family": "Smith", "given": "Ulf", "initials": "U", "orcid": "0000-0002-1439-4608", "affiliations": [], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/908ff4c3bfde48c0a1bdbdd845b765dd.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/908ff4c3bfde48c0a1bdbdd845b765dd"}}, "publications": [{"entity": "publication", "iuid": "d4a02a9125f1428190620dfef3d8f09c", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/d4a02a9125f1428190620dfef3d8f09c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/d4a02a9125f1428190620dfef3d8f09c"}}, "title": "Chronic hyperinsulinemia promotes human hepatocyte senescence.", "authors": [{"family": "Baboota", "given": "Ritesh K", "initials": "RK"}, {"family": "Spinelli", "given": "Rosa", "initials": "R"}, {"family": "Erlandsson", "given": "Malin C", "initials": "MC"}, {"family": "Brandao", "given": "Bruna B", "initials": "BB"}, {"family": "Lino", "given": "Marsel", "initials": "M"}, {"family": "Yang", "given": "Hong", "initials": "H"}, {"family": "Mardinoglu", "given": "Adil", "initials": "A", "orcid": "0000-0002-4254-6090", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ca58bf2d214047e0ae5e38a42a0f2808.json"}}, {"family": "Bokarewa", "given": "Maria I", "initials": "MI"}, {"family": "Boucher", "given": "Jeremie", "initials": "J"}, {"family": "Kahn", "given": "C Ronald", "initials": "CR"}, {"family": "Smith", "given": "Ulf", "initials": "U", "orcid": "0000-0002-1439-4608", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/908ff4c3bfde48c0a1bdbdd845b765dd.json"}}], "type": "journal article", "published": "2022-10-00", "journal": {"title": "Mol Metab", "issn": "2212-8778", "volume": "64", "pages": "101558", "issn-l": "2212-8778"}, "abstract": "Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes.\n\nUsing fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed.\n\nResults showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes.\n\nOur findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.", "doi": "10.1016/j.molmet.2022.101558", "pmid": "35872305", "labels": {"Adil Mardinoglu": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pmc", "key": "PMC9364104"}, {"db": "pii", "key": "S2212-8778(22)00127-2"}], "notes": [], "created": "2023-12-04T15:02:01.209Z", "modified": "2025-04-29T07:09:15.254Z"}, {"entity": "publication", "iuid": "8b8fb21585b14fcdb6b49e0ae3cca926", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/8b8fb21585b14fcdb6b49e0ae3cca926.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/8b8fb21585b14fcdb6b49e0ae3cca926"}}, "title": "BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH.", "authors": [{"family": "Baboota", "given": "Ritesh K", "initials": "RK"}, {"family": "Rawshani", "given": "Aidin", "initials": "A"}, {"family": "Bonnet", "given": "Laurianne", "initials": "L"}, {"family": "Li", "given": "Xiangyu", "initials": "X", "orcid": "0000-0002-8301-9959", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5c452ad4e8bb4302a572693103742047.json"}}, {"family": "Yang", "given": "Hong", "initials": "H"}, {"family": "Mardinoglu", "given": "Adil", "initials": "A"}, {"family": "Tchkonia", "given": "Tamar", "initials": "T", "orcid": "0000-0003-4623-7145", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/190bea8a95ab4008abdb810dff857198.json"}}, {"family": "Kirkland", "given": "James L", "initials": "JL", "orcid": "0000-0003-1676-4905", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d0210f3779854f92a4b1c80003be052f.json"}}, {"family": "Hoffmann", "given": "Anne", "initials": "A"}, {"family": "Dietrich", "given": "Arne", "initials": "A"}, {"family": "Boucher", "given": "Jeremie", "initials": "J"}, {"family": "Bl\u00fcher", "given": "Matthias", "initials": "M", "orcid": "0000-0003-0208-2065", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/587f009a96714fa3910730cf316b5031.json"}}, {"family": "Smith", "given": "Ulf", "initials": "U", "orcid": "0000-0002-1439-4608", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/908ff4c3bfde48c0a1bdbdd845b765dd.json"}}], "type": "journal article", "published": "2022-08-00", "journal": {"title": "Nat Metab", "issn": "2522-5812", "volume": "4", "issue": "8", "pages": "1007-1021", "issn-l": "2522-5812"}, "abstract": "The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.", "doi": "10.1038/s42255-022-00620-x", "pmid": "35995996", "labels": {"Adil Mardinoglu": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pmc", "key": "PMC9398907"}, {"db": "pii", "key": "10.1038/s42255-022-00620-x"}], "notes": [], "created": "2023-12-04T14:58:12.238Z", "modified": "2023-12-04T14:58:12.414Z"}, {"entity": "publication", "iuid": "3698d2df13c2456fa8183f2cedd88a0c", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3698d2df13c2456fa8183f2cedd88a0c.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3698d2df13c2456fa8183f2cedd88a0c"}}, "title": "Adipose tissue morphology, imaging and metabolomics predicting cardiometabolic risk and family history of type 2 diabetes in non-obese men.", "authors": [{"family": "Rawshani", "given": "Aidin", "initials": "A"}, {"family": "Eliasson", "given": "Bj\u00f6rn", "initials": "B"}, {"family": "Rawshani", "given": "Araz", "initials": "A"}, {"family": "Henninger", "given": "Josefin", "initials": "J"}, {"family": "Mardinoglu", "given": "Adil", "initials": "A", "orcid": "0000-0002-4254-6090", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ca58bf2d214047e0ae5e38a42a0f2808.json"}}, {"family": "Carlsson", "given": "\u00c5sa", "initials": "\u00c5"}, {"family": "Sohlin", "given": "Maja", "initials": "M"}, {"family": "Ljungberg", "given": "Maria", "initials": "M", "orcid": "0000-0001-8991-2353", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/4a9eaa8c127245bc967e10bee01fa62c.json"}}, {"family": "Hammarstedt", "given": "Ann", "initials": "A"}, {"family": "Rosengren", "given": "Annika", "initials": "A"}, {"family": "Smith", "given": "Ulf", "initials": "U", "orcid": "0000-0002-1439-4608", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/908ff4c3bfde48c0a1bdbdd845b765dd.json"}}], "type": "journal article", "published": "2020-06-19", "journal": {"title": "Sci Rep", "issn": "2045-2322", "issn-l": "2045-2322", "volume": "10", "issue": "1", "pages": "9973"}, "abstract": "We evaluated the importance of body composition, amount of subcutaneous and visceral fat, liver and heart ectopic fat, adipose tissue distribution and cell size as predictors of cardio-metabolic risk in 53 non-obese male individuals. Known family history of type 2 diabetes was identified in 25 individuals. The participants also underwent extensive phenotyping together with measuring different biomarkers and non-targeted serum metabolomics. We used ensemble learning and other machine learning approaches to identify predictors with considerable relative importance and their intricate interactions. Visceral fat and age were strong individual predictors of ectopic fat accumulation in liver and heart along with markers of lipid oxidation and reduced glucose tolerance. Subcutaneous adipose cell size was the strongest individual predictor of whole-body insulin sensitivity and also a marker of visceral and ectopic fat accumulation. The metabolite 3-MOB along with related branched-chain amino acids demonstrated strong predictability for family history of type 2 diabetes.", "doi": "10.1038/s41598-020-66199-z", "pmid": "32561768", "labels": {"Adil Mardinoglu": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pii", "key": "10.1038/s41598-020-66199-z"}, {"db": "pmc", "key": "PMC7305301"}], "notes": [], "created": "2020-11-30T03:13:14.527Z", "modified": "2022-11-04T11:32:14.827Z"}, {"entity": "publication", "iuid": "2097ed84f9f1453bba48b16b6892addb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/2097ed84f9f1453bba48b16b6892addb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/2097ed84f9f1453bba48b16b6892addb"}}, "title": "Systems biology in hepatology: approaches and applications.", "authors": [{"family": "Mardinoglu", "given": "Adil", "initials": "A", "orcid": "0000-0002-4254-6090", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ca58bf2d214047e0ae5e38a42a0f2808.json"}}, {"family": "Boren", "given": "Jan", "initials": "J", "orcid": "0000-0003-0786-8091", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/73a770eb9e614448a046b8e9199052e9.json"}}, {"family": "Smith", "given": "Ulf", "initials": "U", "orcid": "0000-0002-1439-4608", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/908ff4c3bfde48c0a1bdbdd845b765dd.json"}}, {"family": "Uhlen", "given": "Mathias", "initials": "M", "orcid": "0000-0002-4858-8056", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9ea446aa574042a295d5f69437402f76.json"}}, {"family": "Nielsen", "given": "Jens", "initials": "J"}], "type": "journal article", "published": "2018-06-00", "journal": {"title": "Nat Rev Gastroenterol Hepatol", "issn": "1759-5053", "issn-l": "1759-5045", "volume": "15", "issue": "6", "pages": "365-377"}, "abstract": "Detailed insights into the biological functions of the liver and an understanding of its crosstalk with other human tissues and the gut microbiota can be used to develop novel strategies for the prevention and treatment of liver-associated diseases, including fatty liver disease, cirrhosis, hepatocellular carcinoma and type 2 diabetes mellitus. Biological network models, including metabolic, transcriptional regulatory, protein-protein interaction, signalling and co-expression networks, can provide a scaffold for studying the biological pathways operating in the liver in connection with disease development in a systematic manner. Here, we review studies in which biological network models were used to integrate multiomics data to advance our understanding of the pathophysiological responses of complex liver diseases. We also discuss how this mechanistic approach can contribute to the discovery of potential biomarkers and novel drug targets, which might lead to the design of targeted and improved treatment strategies. Finally, we present a roadmap for the successful integration of models of the liver and other human tissues with the gut microbiota to simulate whole-body metabolic functions in health and disease.", "doi": "10.1038/s41575-018-0007-8", "pmid": "29686404", "labels": {"Affiliated researcher": null, "Adil Mardinoglu": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pii", "key": "10.1038/s41575-018-0007-8"}], "notes": [], "created": "2018-12-03T14:46:27.697Z", "modified": "2022-11-04T11:32:17.573Z"}]}