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

Abstract

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. Intestinal lipid metabolism has a crucial role in metabolic diseases, with transmembrane protein 135 (TMEM135) emerging as a key player in this process. This study reveals that TMEM135 deficiency enhances lipid absorption and utilization in the intestine, addressing the previously unexplored role of TMEM135 in intestinal lipid metabolism. Using CRISPR–Cas9 technology, researchers created TMEM135 KO mice to study lipid uptake and oxidation. They found that TMEM135 deficiency increases long-chain fatty acid uptake without causing lipid accumulation, owing to enhanced lipid oxidation. This process is mediated by CD36, a lipid transporter, and peroxisome proliferator-activated receptor alpha, a transcription factor activated by ELOVL6 and oleoylethanolamide. The study highlights the importance of TMEM135 in maintaining lipid homeostasis and suggests potential therapeutic targets for metabolic diseases. Future research could explore the role of TMEM135 in other tissues and its potential as a therapeutic target. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.