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<p>Excessive lipid accumulation impairs digestion and gastrointestinal function. Transmembrane protein 135 (TMEM135) is involved in lipid metabolism of various tissues. Here, TMEM135 deficiency increased intestinal lipid absorption through ELOVL6-dependent oleoylethanolamide production and subsequent activation of peroxisome proliferator-activated receptor alpha (PPARα), which upregulated CD36 at the plasma membrane in the intestine of mice fed a high-fat diet or lard oil. Despite this enhanced lipid uptake, long-term lipid accumulation was suppressed by elevated peroxisomal and mitochondrial β-oxidation through increased fatty acid oxidation and oxidative phosphorylation activities without chylomicron secretion in TMEM135-depleted intestine. Inhibition of PPARα or ELOVL6 attenuated these effects. Furthermore, consistent results were observed in both TMEM135 KO and intestine-specific TMEM135<sup>iKO</sup> mice, confirming tissue-specific rather than systemic effects. Overall, these results provide insight into the role of TMEM135 as a regulatory node connecting intestinal lipid absorption and systemic energy expenditure, contributing to the coordination between lipid storage and oxidation during metabolic adaptation.</p><p></p>

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TMEM135 deficiency prevents intestinal lipid accumulation by coordinating lipid uptake and oxidation through ELOVL6-mediated PPARα activation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

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  • Hyunsoo Kim,
  • Channy Park,
  • Xiaofan Wei,
  • Arun Chhetri,
  • Laxman Manandhar,
  • Jiwon Seo,
  • Yoonkyung Park,
  • Sang-Wook Lee,
  • Raekil Park

摘要

Excessive lipid accumulation impairs digestion and gastrointestinal function. Transmembrane protein 135 (TMEM135) is involved in lipid metabolism of various tissues. Here, TMEM135 deficiency increased intestinal lipid absorption through ELOVL6-dependent oleoylethanolamide production and subsequent activation of peroxisome proliferator-activated receptor alpha (PPARα), which upregulated CD36 at the plasma membrane in the intestine of mice fed a high-fat diet or lard oil. Despite this enhanced lipid uptake, long-term lipid accumulation was suppressed by elevated peroxisomal and mitochondrial β-oxidation through increased fatty acid oxidation and oxidative phosphorylation activities without chylomicron secretion in TMEM135-depleted intestine. Inhibition of PPARα or ELOVL6 attenuated these effects. Furthermore, consistent results were observed in both TMEM135 KO and intestine-specific TMEM135iKO mice, confirming tissue-specific rather than systemic effects. Overall, these results provide insight into the role of TMEM135 as a regulatory node connecting intestinal lipid absorption and systemic energy expenditure, contributing to the coordination between lipid storage and oxidation during metabolic adaptation.