{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T17:22:17Z","timestamp":1785172937988,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,23]]},"group-title":"Cell Biology","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["R01 EY022086"],"award-info":[{"award-number":["R01 EY022086"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["R01 EY030513"],"award-info":[{"award-number":["R01 EY030513"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["P30 EY016665"],"award-info":[{"award-number":["P30 EY016665"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,23]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  TMEM135 has been implicated in lipid metabolism, but its role in regulating hepatic lipid homeostasis remains unclear. Here, we investigated how TMEM135 affects hepatic lipid metabolism using\n                  <jats:italic>Tmem135<\/jats:italic>\n                  mutant mice with liver-specific\n                  <jats:italic>Pex5<\/jats:italic>\n                  deletion. The\n                  <jats:italic>Tmem135<\/jats:italic>\n                  mutation induced a lipogenic state characterized by depletion of docosahexaenoic acid (DHA), activation of SREBP-dependent pathways, and increased monounsaturated fatty acids without causing hepatic steatosis. In contrast, loss of PEX5-dependent peroxisomal function in\n                  <jats:italic>Tmem135<\/jats:italic>\n                  mutant mice resulted in marked hepatic lipid accumulation, indicating that peroxisomal metabolism buffers the elevated lipogenic state. Fish oil supplementation to\n                  <jats:italic>Tmem135<\/jats:italic>\n                  mutant mice restored DHA levels and suppressed lipogenesis. Proteomics identified distinct DHA-sensitive metabolic programs, including activation of SREBP-dependent lipogenesis. Quantitative malonyl-proteomics revealed increased malonylation of glycolytic enzymes, accompanied by altered glycolytic output. Together, these findings identify TMEM135 as a central regulator of hepatic lipid metabolism and uncover a coordinated mechanism linking lipid availability, lipogenesis, and post-translational metabolic regulation.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlight<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Tmem135<\/jats:italic>\n                    mutation induces a lipogenic state with increased lipolysis without hepatic steatosis. PEX5-dependent peroxisomal function buffers lipid accumulation in\n                    <jats:italic>Tmem135<\/jats:italic>\n                    mutant liver.\n                  <\/jats:p>\n                  <jats:p>\n                    Fish oil supplementation restores DHA and suppresses SREBP-dependent lipogenesis in\n                    <jats:italic>Tmem135<\/jats:italic>\n                    mutants.\n                  <\/jats:p>\n                  <jats:p>\n                    DHA-sensitive protein malonylation targets glycolytic enzymes in\n                    <jats:italic>Tmem135<\/jats:italic>\n                    mutant liver.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.22.740069","type":"posted-content","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T14:15:12Z","timestamp":1784816112000},"source":"Crossref","is-referenced-by-count":0,"title":["TMEM135 deficiency remodels hepatic lipid homeostasis and protein malonylation through a DHA-sensitive lipogenic program buffered by peroxisomal metabolism"],"prefix":"10.64898","author":[{"given":"Ryo","family":"Hagimori","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Landowski","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purnima","family":"Gogoi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Brush","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Bonvicino","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 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