Abstract
Thimet oligopeptidase (EC 3.4.24.15; EP24.15; THOP1) is a potential therapeutic target, as it plays key biological functions in processing biologically functional peptides. The structural conformation of THOP1 provides a unique restriction regarding substrate size, in that it only hydrolyzes peptides (optimally, those ranging from eight to 12 amino acids) and not proteins. The proteasome activity of hydrolyzing proteins releases a large number of intracellular peptides, providing THOP1 substrates within cells. The present study aimed to investigate the possible function of THOP1 in the development of diet-induced obesity (DIO) and insulin resistance by utilizing a murine model of hyperlipidic DIO with both C57BL6 wild-type (WT) and THOP1 null (THOP1−/−) mice. After 24 weeks of being fed a hyperlipidic diet (HD), THOP1−/− and WT mice ingested similar chow and calories; however, the THOP1−/− mice gained 75% less body weight and showed neither insulin resistance nor non-alcoholic fatty liver steatosis when compared to WT mice. THOP1−/− mice had increased adrenergic-stimulated adipose tissue lipolysis as well as a balanced level of expression of genes and microRNAs associated with energy metabolism, adipogenesis, or inflammation. Altogether, these differences converge to a healthy phenotype of THOP1−/− fed a HD. The molecular mechanism that links THOP1 to energy metabolism is suggested herein to involve intracellular peptides, of which the relative levels were identified to change in the adipose tissue of WT and THOP1−/− mice. Intracellular peptides were observed by molecular modeling to interact with both pre-miR-143 and pre-miR-222, suggesting a possible novel regulatory mechanism for gene expression. Therefore, we successfully demonstrated the previously anticipated relevance of THOP1 in energy metabolism regulation. It was suggested that intracellular peptides were responsible for mediating the phenotypic differences that are described herein by a yet unknown mechanism of action.
Highlights
Mammalian proteasomes play essential functions in degrading proteins [1]
An evolutionary ancient function must exist for peptides processed by proteasomes, considering that active proteasomes are found in prokaryotes, while major histocompatibility class I (MHC-I) is only found in cartilaginous fish [3,4,5,6] and not in earlier, more primitive species
These data were recently corroborated by THOP1 C57BL6 null mice (THOP1−/−), which showed poor clinical scores compared to wild-type C57BL6 mice (WT) in an autoimmune encephalomyelitis neurodegeneration model for multiple sclerosis [54]
Summary
Mammalian proteasomes play essential functions in degrading proteins [1]. Proteasomes are important in the processing of peptides for major histocompatibility class I (MHC-I) antigen presentation [2]. THOP1 has been established as one of the highly expressed genes related to epigenetic interactions in lung adenocarcinoma of poor prognosis [44]; it is associated with MHC-I antigen presentation [26,27,45,46,47] and the inactivation of several neuropeptides [41,42,48,49,50,51,52,53]. Intracellular peptides were previously shown to have multiple functions, both inside and outside cells [65], such as facilitating glucose uptake [66] and activating fat metabolism [10,67]
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