Publications

2016
Amy K Rines, Sharabi, Kfir , Tavares, Clint DJ, and Puigserver, Pere . 2016. Targeting Hepatic Glucose Metabolism In The Treatment Of Type 2 Diabetes. Nat Rev Drug Discov, 15, 11, Pp. 786-804. doi:10.1038/nrd.2016.151. Abstract
Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycaemia. Although current diabetes treatments have exhibited some success in lowering blood glucose levels, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycaemia. Novel antidiabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.
2015
Kfir Sharabi, Tavares, Clint DJ, Rines, Amy K, and Puigserver, Pere . 2015. Molecular Pathophysiology Of Hepatic Glucose Production. Mol Aspects Med, 46, Pp. 21-33. doi:10.1016/j.mam.2015.09.003. Abstract
Maintaining blood glucose concentration within a relatively narrow range through periods of fasting or excess nutrient availability is essential to the survival of the organism. This is achieved through an intricate balance between glucose uptake and endogenous glucose production to maintain constant glucose concentrations. The liver plays a major role in maintaining normal whole body glucose levels by regulating the processes of de novo glucose production (gluconeogenesis) and glycogen breakdown (glycogenolysis), thus controlling the levels of hepatic glucose release. Aberrant regulation of hepatic glucose production (HGP) can result in deleterious clinical outcomes, and excessive HGP is a major contributor to the hyperglycemia observed in Type 2 diabetes mellitus (T2DM). Indeed, adjusting glycemia as close as possible to a non-diabetic range is the foremost objective in the medical treatment of patients with T2DM and is currently achieved in the clinic primarily through suppression of HGP. Here, we review the molecular mechanisms controlling HGP in response to nutritional and hormonal signals and discuss how these signals are altered in T2DM.
K. Sharabi, Tavares, C. D. , Rines, A. K. , and Puigserver, P. . 2015. Molecular Pathophysiology Of Hepatic Glucose Production. Mol Aspects Med, 46, Pp. 21-33. Abstract
Maintaining blood glucose concentration within a relatively narrow range through periods of fasting or excess nutrient availability is essential to the survival of the organism. This is achieved through an intricate balance between glucose uptake and endogenous glucose production to maintain constant glucose concentrations. The liver plays a major role in maintaining normal whole body glucose levels by regulating the processes of de novo glucose production (gluconeogenesis) and glycogen breakdown (glycogenolysis), thus controlling the levels of hepatic glucose release. Aberrant regulation of hepatic glucose production (HGP) can result in deleterious clinical outcomes, and excessive HGP is a major contributor to the hyperglycemia observed in Type 2 diabetes mellitus (T2DM). Indeed, adjusting glycemia as close as possible to a non-diabetic range is the foremost objective in the medical treatment of patients with T2DM and is currently achieved in the clinic primarily through suppression of HGP. Here, we review the molecular mechanisms controlling HGP in response to nutritional and hormonal signals and discuss how these signals are altered in T2DM.
Carbon dioxide (CO2) is a key molecule in many biological processes. Studies in humans, mice, D. melanogaster, C. elegans, unicellular organisms and plants have shed light on the molecular pathways activated by elevated levels of CO2. However, the mechanisms that organisms use to sense and respond to high CO2 levels remain largely unknown. Previous work has shown that C. elegans quickly avoid elevated CO2 levels using mechanisms that involve the BAG, ASE and AFD neurons via cGMP- and calcium- signaling pathways. Here, we discuss our recent finding that exposure of C. elegans to high CO2 levels leads to a very rapid cessation in the contraction of the pharynx muscles. Surprisingly, none of the tested CO2 avoidance mutants affected the rapid pumping inhibition response to elevated CO2 levels. A forward genetic screen identified that the hid-1-mediated pathway of dense core vesicle maturation regulates the pumping inhibition, probably through affecting neuropeptide secretion. Genetic studies and laser ablation experiments showed that the CO2 response of the pharyngeal muscle pumping is regulated by the BAG neurons, the same neurons that mediate CO2 avoidance.
Kfir Sharabi, Charar, Chayki , and Gruenbaum, Yosef . 2015. Pharyngeal Pumping Inhibition And Avoidance By Acute Exposure To High Co2 Levels Are Both Regulated By The Bag Neurons Via Different Molecular Pathways. Worm, 4, 1, Pp. e1008898. doi:10.1080/21624054.2015.1008898. Abstract
Carbon dioxide (CO2) is a key molecule in many biological processes. Studies in humans, mice, D. melanogaster, C. elegans, unicellular organisms and plants have shed light on the molecular pathways activated by elevated levels of CO2. However, the mechanisms that organisms use to sense and respond to high CO2 levels remain largely unknown. Previous work has shown that C. elegans quickly avoid elevated CO2 levels using mechanisms that involve the BAG, ASE and AFD neurons via cGMP- and calcium- signaling pathways. Here, we discuss our recent finding that exposure of C. elegans to high CO2 levels leads to a very rapid cessation in the contraction of the pharynx muscles. Surprisingly, none of the tested CO2 avoidance mutants affected the rapid pumping inhibition response to elevated CO2 levels. A forward genetic screen identified that the hid-1-mediated pathway of dense core vesicle maturation regulates the pumping inhibition, probably through affecting neuropeptide secretion. Genetic studies and laser ablation experiments showed that the CO2 response of the pharyngeal muscle pumping is regulated by the BAG neurons, the same neurons that mediate CO2 avoidance.
2014
Kfir Sharabi, Charar, Chayki , Friedman, Nurit , Mizrahi, Inbar , Zaslaver, Alon , Sznajder, Jacob I, and Gruenbaum, Yosef . 2014. The Response To High Co2 Levels Requires The Neuropeptide Secretion Component Hid-1 To Promote Pumping Inhibition. Plos Genet, 10, 8, Pp. e1004529. doi:10.1371/journal.pgen.1004529. Abstract
Carbon dioxide (CO2) is a key molecule in many biological processes; however, mechanisms by which organisms sense and respond to high CO2 levels remain largely unknown. Here we report that acute CO2 exposure leads to a rapid cessation in the contraction of the pharynx muscles in Caenorhabditis elegans. To uncover the molecular mechanisms underlying this response, we performed a forward genetic screen and found that hid-1, a key component in neuropeptide signaling, regulates this inhibition in muscle contraction. Surprisingly, we found that this hid-1-mediated pathway is independent of any previously known pathways controlling CO2 avoidance and oxygen sensing. In addition, animals with mutations in unc-31 and egl-21 (neuropeptide secretion and maturation components) show impaired inhibition of muscle contraction following acute exposure to high CO2 levels, in further support of our findings. Interestingly, the observed response in the pharynx muscle requires the BAG neurons, which also mediate CO2 avoidance. This novel hid-1-mediated pathway sheds new light on the physiological effects of high CO2 levels on animals at the organism-wide level.
K. Sharabi, Charar, C. , Friedman, N. , Mizrahi, I. , Zaslaver, A. , Sznajder, J. I. , and Gruenbaum, Y. . 2014. The Response To High Co2 Levels Requires The Neuropeptide Secretion Component Hid-1 To Promote Pumping Inhibition. Plos Genet, 10, Pp. e1004529. Abstract
Carbon dioxide (CO2) is a key molecule in many biological processes; however, mechanisms by which organisms sense and respond to high CO2 levels remain largely unknown. Here we report that acute CO2 exposure leads to a rapid cessation in the contraction of the pharynx muscles in Caenorhabditis elegans. To uncover the molecular mechanisms underlying this response, we performed a forward genetic screen and found that hid-1, a key component in neuropeptide signaling, regulates this inhibition in muscle contraction. Surprisingly, we found that this hid-1-mediated pathway is independent of any previously known pathways controlling CO2 avoidance and oxygen sensing. In addition, animals with mutations in unc-31 and egl-21 (neuropeptide secretion and maturation components) show impaired inhibition of muscle contraction following acute exposure to high CO2 levels, in further support of our findings. Interestingly, the observed response in the pharynx muscle requires the BAG neurons, which also mediate CO2 avoidance. This novel hid-1-mediated pathway sheds new light on the physiological effects of high CO2 levels on animals at the organism-wide level.
2012
Rachel Barkan, Zahand, Adam J, Sharabi, Kfir , Lamm, Ayelet T, Feinstein, Naomi , Haithcock, Erin , Wilson, Katherine L, Liu, Jun , and Gruenbaum, Yosef . 2012. Ce-Emerin And Lem-2: Essential Roles In Caenorhabditis Elegans Development, Muscle Function, And Mitosis. Mol Biol Cell, 23, 4, Pp. 543-52. doi:10.1091/mbc.E11-06-0505. Abstract
Emerin and LEM2 are ubiquitous inner nuclear membrane proteins conserved from humans to Caenorhabditis elegans. Loss of human emerin causes Emery-Dreifuss muscular dystrophy (EDMD). To test the roles of emerin and LEM2 in somatic cells, we used null alleles of both genes to generate C. elegans animals that were either hypomorphic (LEM-2-null and heterozygous for Ce-emerin) or null for both proteins. Single-null and hypomorphic animals were viable and fertile. Double-null animals used the maternal pool of Ce-emerin to develop to the larval L2 stage, then arrested. Nondividing somatic cell nuclei appeared normal, whereas dividing cells had abnormal nuclear envelope and chromatin organization and severe defects in postembryonic cell divisions, including the mesodermal lineage. Life span was unaffected by loss of Ce-emerin alone but was significantly reduced in LEM-2-null animals, and double-null animals had an even shorter life span. In addition to striated muscle defects, double-null animals and LEM-2-null animals showed unexpected defects in smooth muscle activity. These findings implicate human LEM2 mutations as a potential cause of EDMD and further suggest human LEM2 mutations might cause distinct disorders of greater severity, since C. elegans lacking only LEM-2 had significantly reduced life span and smooth muscle activity.
R. Barkan, Zahand, A. J. , Sharabi, K. , Lamm, A. T. , Feinstein, N. , Haithcock, E. , Wilson, K. L. , Liu, J. , and Gruenbaum, Y. . 2012. Ce-Emerin And Lem-2: Essential Roles In Caenorhabditis Elegans Development, Muscle Function, And Mitosis. Mol Biol Cell, 23, Pp. 543-52. Abstract
Emerin and LEM2 are ubiquitous inner nuclear membrane proteins conserved from humans to Caenorhabditis elegans. Loss of human emerin causes Emery-Dreifuss muscular dystrophy (EDMD). To test the roles of emerin and LEM2 in somatic cells, we used null alleles of both genes to generate C. elegans animals that were either hypomorphic (LEM-2-null and heterozygous for Ce-emerin) or null for both proteins. Single-null and hypomorphic animals were viable and fertile. Double-null animals used the maternal pool of Ce-emerin to develop to the larval L2 stage, then arrested. Nondividing somatic cell nuclei appeared normal, whereas dividing cells had abnormal nuclear envelope and chromatin organization and severe defects in postembryonic cell divisions, including the mesodermal lineage. Life span was unaffected by loss of Ce-emerin alone but was significantly reduced in LEM-2-null animals, and double-null animals had an even shorter life span. In addition to striated muscle defects, double-null animals and LEM-2-null animals showed unexpected defects in smooth muscle activity. These findings implicate human LEM2 mutations as a potential cause of EDMD and further suggest human LEM2 mutations might cause distinct disorders of greater severity, since C. elegans lacking only LEM-2 had significantly reduced life span and smooth muscle activity.
I. Vadasz, Dada, L. A. , Briva, A. , Helenius, I. T. , Sharabi, K. , Welch, L. C. , Kelly, A. M. , Grzesik, B. A. , Budinger, G. R. , Liu, J. , Seeger, W. , Beitel, G. J. , Gruenbaum, Y. , and Sznajder, J. I. . 2012. Evolutionary Conserved Role Of C-Jun-N-Terminal Kinase In Co2-Induced Epithelial Dysfunction. Plos One, 7, Pp. e46696. Abstract
Elevated CO(2) levels (hypercapnia) occur in patients with respiratory diseases and impair alveolar epithelial integrity, in part, by inhibiting Na,K-ATPase function. Here, we examined the role of c-Jun N-terminal kinase (JNK) in CO(2) signaling in mammalian alveolar epithelial cells as well as in diptera, nematodes and rodent lungs. In alveolar epithelial cells, elevated CO(2) levels rapidly induced activation of JNK leading to downregulation of Na,K-ATPase and alveolar epithelial dysfunction. Hypercapnia-induced activation of JNK required AMP-activated protein kinase (AMPK) and protein kinase C-zeta leading to subsequent phosphorylation of JNK at Ser-129. Importantly, elevated CO(2) levels also caused a rapid and prominent activation of JNK in Drosophila S2 cells and in C. elegans. Paralleling the results with mammalian epithelial cells, RNAi against Drosophila JNK fully prevented CO(2)-induced downregulation of Na,K-ATPase in Drosophila S2 cells. The importance and specificity of JNK CO(2) signaling was additionally demonstrated by the ability of mutations in the C. elegans JNK homologs, jnk-1 and kgb-2 to partially rescue the hypercapnia-induced fertility defects but not the pharyngeal pumping defects. Together, these data provide evidence that deleterious effects of hypercapnia are mediated by JNK which plays an evolutionary conserved, specific role in CO(2) signaling in mammals, diptera and nematodes.
István Vadász, Dada, Laura A, Briva, Arturo , Helenius, Iiro Taneli , Sharabi, Kfir , Welch, Lynn C, Kelly, Aileen M, Grzesik, Benno A, Budinger, Scott GR, Liu, Jing , Seeger, Werner , Beitel, Greg J, Gruenbaum, Yosef , and Sznajder, Jacob I. 2012. Evolutionary Conserved Role Of C-Jun-N-Terminal Kinase In Co2-Induced Epithelial Dysfunction. Plos One, 7, 10, Pp. e46696. doi:10.1371/journal.pone.0046696. Abstract
Elevated CO(2) levels (hypercapnia) occur in patients with respiratory diseases and impair alveolar epithelial integrity, in part, by inhibiting Na,K-ATPase function. Here, we examined the role of c-Jun N-terminal kinase (JNK) in CO(2) signaling in mammalian alveolar epithelial cells as well as in diptera, nematodes and rodent lungs. In alveolar epithelial cells, elevated CO(2) levels rapidly induced activation of JNK leading to downregulation of Na,K-ATPase and alveolar epithelial dysfunction. Hypercapnia-induced activation of JNK required AMP-activated protein kinase (AMPK) and protein kinase C-ζ leading to subsequent phosphorylation of JNK at Ser-129. Importantly, elevated CO(2) levels also caused a rapid and prominent activation of JNK in Drosophila S2 cells and in C. elegans. Paralleling the results with mammalian epithelial cells, RNAi against Drosophila JNK fully prevented CO(2)-induced downregulation of Na,K-ATPase in Drosophila S2 cells. The importance and specificity of JNK CO(2) signaling was additionally demonstrated by the ability of mutations in the C. elegans JNK homologs, jnk-1 and kgb-2 to partially rescue the hypercapnia-induced fertility defects but not the pharyngeal pumping defects. Together, these data provide evidence that deleterious effects of hypercapnia are mediated by JNK which plays an evolutionary conserved, specific role in CO(2) signaling in mammals, diptera and nematodes.
2010
Z. S. Azzam, Sharabi, K. , Guetta, J. , Bank, E. M. , and Gruenbaum, Y. . 2010. The Physiological And Molecular Effects Of Elevated Co2 Levels. Cell Cycle, 9, Pp. 1528-32. Abstract
Carbon dioxide (CO2) is an end product of cellular respiration, a process by which organisms including all plants, animals, many fungi and some bacteria obtain energy. CO2 has several physiologic roles in respiration, pH buffering, autoregulation of the blood supply and others. Here we review recent findings from studies in mammalian lung cells, Caenorhabditis elegans and Drosophila melanogaster that help shed light on the molecular sensing and response to hypercapnia.
Zaher S Azzam, Sharabi, Kfir , Guetta, Julia , Bank, Erin M, and Gruenbaum, Yosef . 2010. The Physiological And Molecular Effects Of Elevated Co2 Levels. Cell Cycle, 9, 8, Pp. 1528-32. doi:10.4161/cc.9.8.11196. Abstract
Carbon dioxide (CO2) is an end product of cellular respiration, a process by which organisms including all plants, animals, many fungi and some bacteria obtain energy. CO2 has several physiologic roles in respiration, pH buffering, autoregulation of the blood supply and others. Here we review recent findings from studies in mammalian lung cells, Caenorhabditis elegans and Drosophila melanogaster that help shed light on the molecular sensing and response to hypercapnia.
2009
K. Sharabi, Hurwitz, A. , Simon, A. J. , Beitel, G. J. , Morimoto, R. I. , Rechavi, G. , Sznajder, J. I. , and Gruenbaum, Y. . 2009. Elevated Co2 Levels Affect Development, Motility, And Fertility And Extend Life Span In Caenorhabditis Elegans. Proc Natl Acad Sci U S A, 106, Pp. 4024-9. Abstract
Hypercapnia (high CO(2) levels) occurs in a number of lung diseases and it is associated with worse outcomes in patients with chronic obstructive lung disease (COPD). However, it is largely unknown how hypercapnia is sensed and responds in nonneuronal cells. Here, we used C. elegans to study the response to nonanesthetic CO(2) levels and show that levels exceeding 9% induce aberrant motility that is accompanied by age-dependent deterioration of body muscle organization, slowed development, reduced fertility and increased life span. These effects occur independently of the IGF-R, dietary restriction, egg laying or mitochondrial-induced aging pathways. Transcriptional profiling analysis shows specific and dynamic changes in gene expression after 1, 6, or 72 h of exposure to 19% CO(2) including increased transcription of several 7-transmembrane domain and innate immunity genes and a reduction in transcription of many of the MSP genes. Together, these results suggest specific physiological and molecular responses to hypercapnia, which appear to be independent of early heat shock and HIF mediated pathways.
Kfir Sharabi, Hurwitz, Anat , Simon, Amos J, Beitel, Greg J, Morimoto, Richard I, Rechavi, Gideon , Sznajder, Jacob I, and Gruenbaum, Yosef . 2009. Elevated Co2 Levels Affect Development, Motility, And Fertility And Extend Life Span In Caenorhabditis Elegans. Proc Natl Acad Sci U S A, 106, 10, Pp. 4024-9. doi:10.1073/pnas.0900309106. Abstract
Hypercapnia (high CO(2) levels) occurs in a number of lung diseases and it is associated with worse outcomes in patients with chronic obstructive lung disease (COPD). However, it is largely unknown how hypercapnia is sensed and responds in nonneuronal cells. Here, we used C. elegans to study the response to nonanesthetic CO(2) levels and show that levels exceeding 9% induce aberrant motility that is accompanied by age-dependent deterioration of body muscle organization, slowed development, reduced fertility and increased life span. These effects occur independently of the IGF-R, dietary restriction, egg laying or mitochondrial-induced aging pathways. Transcriptional profiling analysis shows specific and dynamic changes in gene expression after 1, 6, or 72 h of exposure to 19% CO(2) including increased transcription of several 7-transmembrane domain and innate immunity genes and a reduction in transcription of many of the MSP genes. Together, these results suggest specific physiological and molecular responses to hypercapnia, which appear to be independent of early heat shock and HIF mediated pathways.
Kfir Sharabi, Lecuona, Emilia , Helenius, Iiro Taneli , Beitel, Greg J, Sznajder, Jacob Iasha , and Gruenbaum, Yosef . 2009. Sensing, Physiological Effects And Molecular Response To Elevated Co2 Levels In Eukaryotes. J Cell Mol Med, 13, 11-12, Pp. 4304-18. doi:10.1111/j.1582-4934.2009.00952.x. Abstract
Carbon dioxide (CO(2)) is an important gaseous molecule that maintains biosphere homeostasis and is an important cellular signalling molecule in all organisms. The transport of CO(2) through membranes has fundamental roles in most basic aspects of life in both plants and animals. There is a growing interest in understanding how CO(2) is transported into cells, how it is sensed by neurons and other cell types and in understanding the physiological and molecular consequences of elevated CO(2) levels (hypercapnia) at the cell and organism levels. Human pulmonary diseases and model organisms such as fungi, C. elegans, Drosophila and mice have been proven to be important in understanding of the mechanisms of CO(2) sensing and response.
K. Sharabi, Lecuona, E. , Helenius, I. T. , Beitel, G. J. , Sznajder, J. I. , and Gruenbaum, Y. . 2009. Sensing, Physiological Effects And Molecular Response To Elevated Co2 Levels In Eukaryotes. J Cell Mol Med, 13, Pp. 4304-18. Abstract
Carbon dioxide (CO(2)) is an important gaseous molecule that maintains biosphere homeostasis and is an important cellular signalling molecule in all organisms. The transport of CO(2) through membranes has fundamental roles in most basic aspects of life in both plants and animals. There is a growing interest in understanding how CO(2) is transported into cells, how it is sensed by neurons and other cell types and in understanding the physiological and molecular consequences of elevated CO(2) levels (hypercapnia) at the cell and organism levels. Human pulmonary diseases and model organisms such as fungi, C. elegans, Drosophila and mice have been proven to be important in understanding of the mechanisms of CO(2) sensing and response.

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