{"entity": "researcher", "timestamp": "2026-06-08T11:22:34.235Z", "family": "Henricsson", "given": "Marcus", "initials": "M", "orcid": "0000-0002-4202-0339", "affiliations": ["Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg 40530, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/e0fbd663456e4767acbfbe87f79a930b.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/e0fbd663456e4767acbfbe87f79a930b"}}, "publications": [{"entity": "publication", "iuid": "1ec4aea248e54794acb926703e7b5385", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/1ec4aea248e54794acb926703e7b5385.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/1ec4aea248e54794acb926703e7b5385"}}, "title": "Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.", "authors": [{"family": "Laudette", "given": "Marion", "initials": "M"}, {"family": "Lindbom", "given": "Malin", "initials": "M"}, {"family": "Arif", "given": "Muhammad", "initials": "M", "orcid": "0000-0003-2261-0881", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c8ffc9889ace44e3b992816601b817e2.json"}}, {"family": "Cinato", "given": "Mathieu", "initials": "M", "orcid": "0000-0002-8490-4335", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5b2d3790356a446e85061a007b50bb28.json"}}, {"family": "Ruiz", "given": "Mario", "initials": "M"}, {"family": "Doran", "given": "Stephen", "initials": "S", "orcid": "0000-0002-9236-5407", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/836142c593f64f98a4c5a5ea20663485.json"}}, {"family": "Miljanovic", "given": "Azra", "initials": "A"}, {"family": "Rutberg", "given": "Mikael", "initials": "M"}, {"family": "Andersson", "given": "Linda", "initials": "L"}, {"family": "Klevstig", "given": "Martina", "initials": "M"}, {"family": "Henricsson", "given": "Marcus", "initials": "M", "orcid": "0000-0002-4202-0339", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e0fbd663456e4767acbfbe87f79a930b.json"}}, {"family": "Bergh", "given": "Per-Olof", "initials": "PO"}, {"family": "Bollano", "given": "Entela", "initials": "E"}, {"family": "Aung", "given": "Nay", "initials": "N", "orcid": "0000-0001-5095-1611", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/741c9417ac1d451c8f6fcd4adfa7b78a.json"}}, {"family": "Gustav Smith", "given": "J", "initials": "J"}, {"family": "Pilon", "given": "Marc", "initials": "M"}, {"family": "Hy\u00f6tyl\u00e4inen", "given": "Tuulia", "initials": "T", "orcid": "0000-0002-1389-8302", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fc08a199297b42afa85e07adc381a8f4.json"}}, {"family": "Ore\u0161i\u010d", "given": "Matej", "initials": "M"}, {"family": "Perkins", "given": "Rosie", "initials": "R"}, {"family": "Mardinoglu", "given": "Adil", "initials": "A"}, {"family": "Levin", "given": "Malin C", "initials": "MC"}, {"family": "Bor\u00e9n", "given": "Jan", "initials": "J", "orcid": "0000-0003-0786-8091", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/73a770eb9e614448a046b8e9199052e9.json"}}], "type": "journal article", "published": "2023-07-04", "journal": {"title": "Cardiovasc Res", "issn": "1755-3245", "volume": "119", "issue": "7", "pages": "1537-1552", "issn-l": null}, "abstract": "Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells.\n\nMice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism.\n\nPCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.", "doi": "10.1093/cvr/cvad041", "pmid": "36880401", "labels": {"Adil Mardinoglu": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pmc", "key": "PMC10318396"}, {"db": "pii", "key": "7070420"}], "notes": [], "created": "2023-12-04T14:52:58.422Z", "modified": "2023-12-04T14:52:58.663Z"}, {"entity": "publication", "iuid": "e42414db412d45758a0c40e86bad9d59", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/e42414db412d45758a0c40e86bad9d59.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/e42414db412d45758a0c40e86bad9d59"}}, "title": "Glucosylceramide synthase deficiency in the heart compromises \u03b21-adrenergic receptor trafficking.", "authors": [{"family": "Andersson", "given": "Linda", "initials": "L"}, {"family": "Cinato", "given": "Mathieu", "initials": "M", "orcid": "0000-0002-8490-4335", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5b2d3790356a446e85061a007b50bb28.json"}}, {"family": "Mardani", "given": "Ismena", "initials": "I"}, {"family": "Miljanovic", "given": "Azra", "initials": "A"}, {"family": "Arif", "given": "Muhammad", "initials": "M", "orcid": "0000-0003-2261-0881", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/c8ffc9889ace44e3b992816601b817e2.json"}}, {"family": "Koh", "given": "Ara", "initials": "A", "orcid": "0000-0001-7673-034X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b3dd91ff18d24c8a9d1369bd1c6c28fb.json"}}, {"family": "Lindbom", "given": "Malin", "initials": "M"}, {"family": "Laudette", "given": "Marion", "initials": "M"}, {"family": "Bollano", "given": "Entela", "initials": "E", "orcid": "0000-0003-3341-2434", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/30e6f290d9094fdb9abbc3e053bd3054.json"}}, {"family": "Omerovic", "given": "Elmir", "initials": "E", "orcid": "0000-0002-3875-8621", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/86ecd8364efe43a2911675790963b8e5.json"}}, {"family": "Klevstig", "given": "Martina", "initials": "M"}, {"family": "Henricsson", "given": "Marcus", "initials": "M", "orcid": "0000-0002-4202-0339", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e0fbd663456e4767acbfbe87f79a930b.json"}}, {"family": "Fogelstrand", "given": "Per", "initials": "P"}, {"family": "Sw\u00e4rd", "given": "Karl", "initials": "K"}, {"family": "Ekstrand", "given": "Matias", "initials": "M", "orcid": "0000-0002-0403-9266", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/36c3e3c2978e467097d8e29deb7b2380.json"}}, {"family": "Levin", "given": "Max", "initials": "M", "orcid": "0000-0001-9676-5582", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7743cfcad6784ae9856e88643dd35f5f.json"}}, {"family": "Wikstr\u00f6m", "given": "Johannes", "initials": "J"}, {"family": "Doran", "given": "Stephen", "initials": "S", "orcid": "0000-0002-9236-5407", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/836142c593f64f98a4c5a5ea20663485.json"}}, {"family": "Hy\u00f6tyl\u00e4inen", "given": "Tuulia", "initials": "T", "orcid": "0000-0002-1389-8302", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/fc08a199297b42afa85e07adc381a8f4.json"}}, {"family": "Sinisalu", "given": "Lisanna", "initials": "L"}, {"family": "Ore\u0161i\u010d", "given": "Matej", "initials": "M", "orcid": "0000-0002-2856-9165", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d38bde57ca0145cda655fe9967ac8a01.json"}}, {"family": "Tivesten", "given": "\u00c5sa", "initials": "\u00c5", "orcid": "0000-0002-8318-0486", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/3cea6421d33a480581a55f5edd6bc954.json"}}, {"family": "Adiels", "given": "Martin", "initials": "M", "orcid": "0000-0002-3667-589X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b13d83037e4149f09db6f7a47e9a6dd9.json"}}, {"family": "Bergo", "given": "Martin O", "initials": "MO", "orcid": "0000-0002-6915-7140", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bdb71f7c401340bab38ab3606934ef89.json"}}, {"family": "Proia", "given": "Richard", "initials": "R", "orcid": "0000-0003-0456-1270", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2213cec582e84ee1b620bb282c9a216c.json"}}, {"family": "Mardinoglu", "given": "Adil", "initials": "A"}, {"family": "Jeppsson", "given": "Anders", "initials": "A", "orcid": "0000-0003-2356-2295", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b429b50a3e7d4b62b4b48323368f36b0.json"}}, {"family": "Bor\u00e9n", "given": "Jan", "initials": "J"}, {"family": "Levin", "given": "Malin C", "initials": "MC"}], "type": "journal article", "published": "2021-11-14", "journal": {"title": "Eur. Heart J.", "issn": "1522-9645", "volume": "42", "issue": "43", "pages": "4481-4492", "issn-l": "0195-668X"}, "abstract": "Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.\n\nUsing human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to \u03b2-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of \u03b21-adrenergic receptors.\n\nOur findings suggest that cardiac glycosphingolipids are required to maintain \u03b2-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.", "doi": "10.1093/eurheartj/ehab412", "pmid": "34297830", "labels": {"Adil Mardinoglu": null, "SciLifeLab Fellow": null}, "xrefs": [{"db": "pmc", "key": "PMC8599074"}, {"db": "pii", "key": "6327090"}], "notes": [], "created": "2023-12-04T15:06:27.939Z", "modified": "2023-12-04T15:06:28.547Z"}]}