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Blood levels of triglycerides and cholesterol are altered in ALS patients and pre-symptomatic gene carriers, but mechanistic insights into these changes are lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Serum samples from sporadic ALS patients (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009118), mutated SOD1 and FUS\/TARDBP (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920, 40, 17, respectively) with age and gender-matched controls (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200996) were analysed for alterations in the angiopoietin-like protein (ANGPTL) system using enzyme-linked immunosorbent assays.\n                      <jats:italic>SOD1<\/jats:italic>\n                      <jats:sup>G93A<\/jats:sup>\n                      murine model was studied at pre-symptomatic (P50), early symptomatic (P90), and fully symptomatic (P110) stages, along with their wild-type (WT) littermates for ANGPTLs. Untargeted lipidomics on serum was performed using high-resolution liquid chromatography-mass spectrometry. Further, the involvement of the hypothalamus was studied using hypothalamic volumetry in patients and an antibody array spanning 308 proteins in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We show that mutation-specific patterns of systemic lipid abnormalities appear in ALS and that they correlate with reduced levels of angiopoietin-like proteins 3 and 4. ANGPTL-3\/4, in turn, correlates with hypothalamic atrophy but not with corticospinal involvement, as determined by MRI volumetry and diffusion tensor imaging. Lipid phenotype and decreased ANGPTL in humans are recapitulated in two\n                      <jats:italic>SOD1<\/jats:italic>\n                      murine ALS models, in which ANGPTL-3, -4, and -8 expression patterns are consistent with the repartitioning of lipid utilisation from muscles to the brown adipose tissue; systemic levels of ANGPTL-3 correlate with hypothalamic neuroinflammation and vascular permeability and with hypothalamic levels of agouti-related protein and neuropeptide Y.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data provide a molecular mechanism linking peripheral lipid metabolism to the dysfunction of a specific hypothalamic circuit through the mediation of systemic ANGPTL-3 and -4. This finding constitutes a molecularly defined entry point to manipulate lipid metabolism in ALS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12916-026-04749-4","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:16:34Z","timestamp":1772579794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Disruption of the angiopoietin-like system connects lipid homeostasis and hypothalamic dysfunction in ALS"],"prefix":"10.1186","volume":"24","author":[{"given":"Sruthi Sankari","family":"Krishnamurthy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana Zardini","family":"Buzatto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caley","family":"Campkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Peter","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Wiesner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Weishaupt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Klose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Wiesenfarth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Elmas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Herrmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zlem","family":"Parlak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelia","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rami","family":"Saad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Weiland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Dupuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Ludolph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kassubek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Dorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Roselli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"4749_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.71","volume":"3","author":"O Hardiman","year":"2017","unstructured":"Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. 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