TMEM135 maintains intestinal lipid homeostasis by regulating lipid uptake and oxidation through ELOVL6-mediated PPARα activation

ABSTRACT: Excessive lipid storage or accumulation impairs digestion and worsen gastrointestinal dysfunction, but the mechanism is not yet fully understood. Transmembrane protein 135 (TMEM135) is involved in lipid metabolism in various tissues. Here, we investigate the role of TMEM135 in intestinal lipid absorption and utilization using in vivo, ex vivo and in vitro models. Depletion of TMEM135 was found to increase intestinal lipid uptake, whereas reduced lipid accumulation in mice fed a HFD or lard oil. TMEM135 deficiency resulted in increased ELOVL6 expression and oleoylethanolamide (OEA) production, which led to transcriptional activation of PPARα in the intestine. The activation of PPARα has two important roles in TMEM135 depleted intestine. First, it upregulates CD36 expression and localization at the plasma membrane, thereby facilitating lipid uptake. Second, it promotes β-oxidation in peroxisomes as well as mitochondria. Overall, TMEM135 depletion increases ELOVL6-mediated OEA production and transcriptional activation of PPARα, which further contributes to lipid homeostasis by regulating intestinal lipid absorption and β-oxidation.

ORGANISM(S): Mus musculus

PROVIDER: GSE291662 | GEO | 2026/09/09

REPOSITORIES: GEO