@article{2ec6f4fc10b94ae4aa3b86d2930dd240,
title = "Transmembrane protein 135 regulates lipid homeostasis through its role in peroxisomal DHA metabolism",
abstract = "Transmembrane protein 135 (TMEM135) is thought to participate in the cellular response to increased intracellular lipids yet no defined molecular function for TMEM135 in lipid metabolism has been identified. In this study, we performed a lipid analysis of tissues from Tmem135 mutant mice and found striking reductions of docosahexaenoic acid (DHA) across all Tmem135 mutant tissues, indicating a role of TMEM135 in the production of DHA. Since all enzymes required for DHA synthesis remain intact in Tmem135 mutant mice, we hypothesized that TMEM135 is involved in the export of DHA from peroxisomes. The Tmem135 mutation likely leads to the retention of DHA in peroxisomes, causing DHA to be degraded within peroxisomes by their beta-oxidation machinery. This may lead to generation or alteration of ligands required for the activation of peroxisome proliferator-activated receptor a (PPARa) signaling, which in turn could result in increased peroxisomal number and beta-oxidation enzymes observed in Tmem135 mutant mice. We confirmed this effect of PPARa signaling by detecting decreased peroxisomes and their proteins upon genetic ablation of Ppara in Tmem135 mutant mice. Using Tmem135 mutant mice, we also validated the protective effect of increased peroxisomes and peroxisomal beta-oxidation on the metabolic disease phenotypes of leptin mutant mice which has been observed in previous studies. Thus, we conclude that TMEM135 has a role in lipid homeostasis through its function in peroxisomes.",
author = "Michael Landowski and Bhute, {Vijesh J.} and Samuel Grindel and Zachary Haugstad and Gyening, {Yeboah K.} and Madison Tytanic and Brush, {Richard S.} and Moyer, {Lucas J.} and Nelson, {David W.} and Davis, {Christopher R.} and Yen, {Chi Liang Eric} and Sakae Ikeda and Agbaga, {Martin Paul} and Akihiro Ikeda",
note = "Funding Information: The authors would like to thank Satoshi Kinoshita and the University of Wisconsin (UW) Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of The Director- NIH (S10OD023526) for the use of facilities and services, as well as Randall Massey and the University of Wisconsin Electron Microscope Core for tissue processing, sectioning, and assistance for this study. Confocal microscopy was performed at the University of Wisconsin-Madison Biochemistry Optical Core, which was established with support from the University of Wisconsin-Madison Department of Biochemistry Endowment. The authors want to recognize the laboratories of Dr. Freya Mowat and Janis Eells for their advice and feedback on this work. The authors would also like to extend their gratitude to Dr. Gregory Barrett-Wilt, Timothy Shriver, and the UW Biotechnology Center{\textquoteright}s Advanced Lipidomics Platform for their time and efforts in optimizing the protocols for our lipidomics experiments. The lipidomics work was supported in part by the UW Comprehensive Diabetes Center Core Services Pilot Award UWCDC-CSPA-20-7 and the UW Office of the Vice Chancellor for Research Graduate Education with funding from the Wisconsin Alumni Research Foundation. This work was also supported by grants from the National Eye Institute (R01EY022086 to A. Ikeda; P30EY016665 to the Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison; NIH T32EY027721 to M. Landowski; F32EY032766 to M. Landowski; R01EY030513 to M-P Agbaga), Timothy William Trout Chairmanship (A. Ikeda), Research to Prevent Blindness Unrestricted grant to Dean McGee Eye Institute (M-P. Agbaga), and NIH grants S10OD028739, R01DK131742, and R01DK124696 (C.L.E.Yen). Funding Information: The authors would like to thank Satoshi Kinoshita and the University of Wisconsin (UW) Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of The Director- NIH (S10OD023526) for the use of facilities and services, as well as Randall Massey and the University of Wisconsin Electron Microscope Core for tissue processing, sectioning, and assistance for this study. Confocal microscopy was performed at the University of Wisconsin-Madison Biochemistry Optical Core, which was established with support from the University of Wisconsin-Madison Department of Biochemistry Endowment. The authors want to recognize the laboratories of Dr. Freya Mowat and Janis Eells for their advice and feedback on this work. The authors would also like to extend their gratitude to Dr. Gregory Barrett-Wilt, Timothy Shriver, and the UW Biotechnology Center{\textquoteright}s Advanced Lipidomics Platform for their time and efforts in optimizing the protocols for our lipidomics experiments. The lipidomics work was supported in part by the UW Comprehensive Diabetes Center Core Services Pilot Award UWCDC-CSPA-20-7 and the UW Office of the Vice Chancellor for Research Graduate Education with funding from the Wisconsin Alumni Research Foundation. This work was also supported by grants from the National Eye Institute (R01EY022086 to A. Ikeda; P30EY016665 to the Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison; NIH T32EY027721 to M. Landowski; F32EY032766 to M. Landowski; R01EY030513 to M-P Agbaga), Timothy William Trout Chairmanship (A. Ikeda), Research to Prevent Blindness Unrestricted grant to Dean McGee Eye Institute (M-P. Agbaga), and NIH grants S10OD028739, R01DK131742, and R01DK124696 (C.L.E.Yen). Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
doi = "10.1038/s42003-022-04404-7",
language = "English",
volume = "6",
journal = "Communications Biology",
issn = "2399-3642",
publisher = "Springer Nature",
number = "1",
}