Abstract
Temporal regulation of nutrient and energy metabolism is emerging as an important aspect of metabolic homeostasis. The regulatory network that integrates the timing cues and nutritional signals to drive diurnal metabolic rhythms remains poorly defined. The 45-kDa isoform of ubiquitin-specific protease 2 (USP2-45) is a deubiquitinase that regulates hepatic gluconeogenesis and glucose metabolism. In this study, we found that USP2-45 is localized to peroxisomes in hepatocytes through a canonical peroxisome-targeting motif at its C-terminus. Clustering analysis indicates that the expression of a subset of peroxisomal genes exhibits robust diurnal rhythm in the liver. Despite this, nuclear hormone receptor PPARα, a known regulator of peroxisome gene expression, does not induce USP2-45 in hepatocytes and is dispensible for its expression during starvation. In contrast, a functional liver clock is required for the proper nutritional and circadian regulation of USP2-45 expression. At the molecular level, transcriptional coactivators PGC-1α and PGC-1β and repressor E4BP4 exert opposing effects on USP2-45 promoter activity. These studies provide insights into the subcellular localization and transcriptional regulation of a clock-controlled deubiquitinase that regulates glucose metabolism.
Highlights
The activities of many metabolic processes in the body are precisely timed and aligned with the body clock [1,2,3,4,5]
We recently reported that USP2-45 regulates hepatic gluconeogenesis and circadian glucose metabolism through modulating the expression of 11b-hydroxysteroid dehydrogenase 1 in the liver [32]
We first employed an in silico approach using the prediction program WoLF PSORT to search for canonical localization signals for various subcellular compartments, including membrane, nucleus, endoplasmic reticulum, mitochondrion, peroxisome, and extracellular space [41]. We found that both UPS2isoforms contain a putative peroxisomal targeting sequence 1 (PTS1) in the C-terminus and are predicted to be localized to peroxisome
Summary
The activities of many metabolic processes in the body are precisely timed and aligned with the body clock [1,2,3,4,5]. Major metabolic pathways involved in hepatic glucose and lipid metabolism, such as glycogenolysis, gluconeogenesis, de novo lipogenesis, and cholesterol biosynthesis, exhibit robust diurnal rhythms in rodents and humans [11,12,13,14]. These cyclic changes of metabolic activities are accompanied with rhythmic expression of a large number of genes involved in nutrient and energy metabolism [15,16,17,18,19]. Perturbations of diurnal metabolic rhythms disrupt normal energy balance and contribute to the pathogenesis of insulin resistance [20,21,22,23]
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