The role of TMEM135 in metabolic homeostasis

Abstract

Excessive lipid storage or accumulation impairs digestion and worsens gastrointestinal dysfunction, however the exact mechanism is not yet fully understood. Transmembrane protein 135 (TMEM135) is known to be involved in lipid metabolism of various tissues. Here, I 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 increased elongation of very long chain fatty acids protein 6 (ELOVL6) expression and oleoylethanolamide (OEA) production, which led to transcriptional activation of PPARα in the intestine. PPARα activation has two important roles in the 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. These results provide insight that intestinal TMEM135 acts as a regulatory node connecting intestinal lipid absorption and systemic energy expenditure, thereby contributing to the coordination between lipid storage and oxidation during metabolic adaptation.