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Tavares, C. D. J. ; Aigner, S. ; Sharabi, K. ; Sathe, S. ; Mutlu, B. ; Yeo, G. W. ; Puigserver, P. Transcriptome-wide analysis of PGC-1 alpha-binding RNAs identifies genes linked to glucagon metabolic action. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020, 117, 22204-22213.Abstract
The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) is a transcriptional coactivator that controls expression of metabolic/energetic genes, programming cellular responses to nutrient and environmental adaptations such as fasting, cold, or exercise. Unlike other coactivators, PGC-1 alpha contains protein domains involved in RNA regulation such as serine/arginine (SR) and RNA recognition motifs (RRM5). However, the RNA targets of PGC-1 alpha and how they pertain to metabolism are unknown. To address this, we performed enhanced ultraviolet (UV) cross-linking and immunoprecipitation followed by sequencing (eCLIP-seq) in primary hepatocytes induced with glucagon. A large fraction of RNAs bound to PGC-1 alpha were intronic sequences of genes involved in transcriptional, signaling, or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional PGC-1 alpha targets such as OXPHOS or gluconeogenic genes. Among the top-scoring RNA sequences bound to PGC-1 alpha were Foxo1, Camk1 delta, Pert, Klf15, Pln4, Cluh, Trpc5, Gfra1, and Slc25a25. PGC-1 alpha depletion decreased a fraction of these glucagon-induced messenger RNA (mRNA) transcript levels. Importantly, knockdown of several of these genes affected glucagon-dependent glucose production, a PGC-1 alpha-regulated metabolic pathway. These studies show that PGC-1 alpha binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.
Cruces-Sande, M. ; Arcones, A. C. ; Vila-Bedmar, R. ; Val-Blasco, A. ; Sharabi, K. ; Díaz-Rodríguez, D. ; Puigserver, P. ; Mayor, F. ; Murga, C. Autophagy mediates hepatic GRK2 degradation to facilitate glucagon-induced metabolic adaptation to fasting. FASEB J 2020, 34, 399-409.Abstract
The liver plays a key role during fasting to maintain energy homeostasis and euglycemia via metabolic processes mainly orchestrated by the insulin/glucagon ratio. We report here that fasting or calorie restriction protocols in C57BL6 mice promote a marked decrease in the hepatic protein levels of G protein-coupled receptor kinase 2 (GRK2), an important negative modulator of both G protein-coupled receptors (GPCRs) and insulin signaling. Such downregulation of GRK2 levels is liver-specific and can be rapidly reversed by refeeding. We find that autophagy, and not the proteasome, represents the main mechanism implicated in fasting-induced GRK2 degradation in the liver in vivo. Reducing GRK2 levels in murine primary hepatocytes facilitates glucagon-induced glucose production and enhances the expression of the key gluconeogenic enzyme Pck1. Conversely, preventing full downregulation of hepatic GRK2 during fasting using adenovirus-driven overexpression of this kinase in the liver leads to glycogen accumulation, decreased glycemia, and hampered glucagon-induced gluconeogenesis, thus preventing a proper and complete adaptation to nutrient deprivation. Overall, our data indicate that physiological fasting-induced downregulation of GRK2 in the liver is key for allowing complete glucagon-mediated responses and efficient metabolic adaptation to fasting in vivo.
Sharabi, K. ; Tavares, C. D. J. ; Puigserver, P. Regulation of Hepatic Metabolism, Recent Advances, and Future Perspectives. Curr Diab Rep 2019, 19, 98.Abstract
PURPOSE OF REVIEW: The purpose of this review is to provide a brief summary of recent advances in our understanding of liver metabolism. The critical role of the liver in controlling whole-body energy homeostasis makes such understanding crucial to efficiently design new treatments for metabolic syndrome diseases, including type 2 diabetes (T2D). RECENT FINDINGS: Significant advances have been made regarding our understanding of the direct and indirect effects of insulin on hepatic metabolism and the communication between the liver and other tissues. Moreover, the catabolic functions of glucagon, as well as the importance of hepatic redox status for the regulation of glucose production, are emerging as potential targets to reduce hyperglycemia. A resolution to the long-standing question "insulin suppression of hepatic glucose production, direct or indirect effect?" is starting to emerge. New advances in our understanding of important fasting-induced hepatic metabolic fluxes may help design better therapies for T2D.
Shigemura, M. ; Lecuona, E. ; Angulo, M. ; Dada, L. A. ; Edwards, M. B. ; Welch, L. C. ; Casalino-Matsuda, M. S. ; Sporn, P. H. S. ; Vadász, I. ; Helenius, I. T. ; et al. Elevated CO regulates the Wnt signaling pathway in mammals, Drosophila melanogaster and Caenorhabditis elegans. Sci Rep 2019, 9 18251.Abstract
Carbon dioxide (CO) is sensed by cells and can trigger signals to modify gene expression in different tissues leading to changes in organismal functions. Despite accumulating evidence that several pathways in various organisms are responsive to CO elevation (hypercapnia), it has yet to be elucidated how hypercapnia activates genes and signaling pathways, or whether they interact, are integrated, or are conserved across species. Here, we performed a large-scale transcriptomic study to explore the interaction/integration/conservation of hypercapnia-induced genomic responses in mammals (mice and humans) as well as invertebrates (Caenorhabditis elegans and Drosophila melanogaster). We found that hypercapnia activated genes that regulate Wnt signaling in mouse lungs and skeletal muscles in vivo and in several cell lines of different tissue origin. Hypercapnia-responsive Wnt pathway homologues were similarly observed in secondary analysis of available transcriptomic datasets of hypercapnia in a human bronchial cell line, flies and nematodes. Our data suggest the evolutionarily conserved role of high CO in regulating Wnt pathway genes.
Hatting, M. ; Tavares, C. D. J. ; Sharabi, K. ; Rines, A. K. ; Puigserver, P. Insulin regulation of gluconeogenesis. Annals of the New York Academy of SciencesAnnals of the New York Academy of SciencesAnn. N.Y. Acad. Sci. 2018, 1411, 21 - 35. Publisher's VersionAbstract
Abstract The coordinated regulation between cellular glucose uptake and endogenous glucose production is indispensable for the maintenance of constant blood glucose concentrations. The liver contributes significantly to this process by altering the levels of hepatic glucose release, through controlling the processes of de novo glucose production (gluconeogenesis) and glycogen breakdown (glycogenolysis). Various nutritional and hormonal stimuli signal to alter hepatic gluconeogenic flux, and suppression of this metabolic pathway during the postprandial state can, to a significant extent, be attributed to insulin. Here, we review some of the molecular mechanisms through which insulin modulates hepatic gluconeogenesis, thus controlling glucose production by the liver to ultimately maintain normoglycemia. Various signaling pathways governed by insulin converge at the level of transcriptional regulation of the key hepatic gluconeogenic genes PCK1 and G6PC, highlighting this as one of the focal mechanisms through which gluconeogenesis is modulated. In individuals with compromised insulin signaling, such as insulin resistance in type 2 diabetes, insulin fails to suppress hepatic gluconeogenesis, even in the fed state; hence, an insight into these insulin-moderated pathways is critical for therapeutic purposes.
Hatting, M. ; Rines, A. K. ; Luo, C. ; Tabata, M. ; Sharabi, K. ; Hall, J. A. ; Verdeguer, F. ; Trautwein, C. ; Puigserver, P. Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting. Cell Metab 2017, 25, 428-437.Abstract
A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high-fat diet intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by the inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet-induced thermogenesis in BAT through increased CREB-dependent expression of UCP1.
Sharabi, K. ; Lin, H. ; Tavares, C. D. J. ; Dominy, J. E. ; Camporez, J. P. ; Perry, R. J. ; Schilling, R. ; Rines, A. K. ; Lee, J. ; Hickey, M. ; et al. Selective Chemical Inhibition of PGC-1α Gluconeogenic Activity Ameliorates Type 2 Diabetes. Cell 2017, 169, 148-160.e15.Abstract
Type 2 diabetes (T2D) is a worldwide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in the liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression, and reduce glucose production in hepatocytes. On the basis of potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity, and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.