The Experts below are selected from a list of 198 Experts worldwide ranked by ideXlab platform
Varman T Samuel - One of the best experts on this subject based on the ideXlab platform.
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hepatic Diacylglycerol associated protein kinase ce translocation links hepatic steatosis to hepatic insulin resistance in humans
Cell Reports, 2017Co-Authors: Kasper W Ter Horst, Pim W Gilijamse, Ruth I Versteeg, Mariette T Ackermans, Aart J Nederveen, Susanne E La Fleur, Johannes A Romijn, Max Nieuwdorp, Dongyan Zhang, Varman T SamuelAbstract:Summary Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic Diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic Diacylglycerols were strongly associated with hepatic PKCe activation, as reflected by PKCe translocation to the plasma membrane. These results demonstrate the relevance of hepatic Diacylglycerol-induced PKCe activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.
Dongyan Zhang - One of the best experts on this subject based on the ideXlab platform.
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hepatic Diacylglycerol associated protein kinase ce translocation links hepatic steatosis to hepatic insulin resistance in humans
Cell Reports, 2017Co-Authors: Kasper W Ter Horst, Pim W Gilijamse, Ruth I Versteeg, Mariette T Ackermans, Aart J Nederveen, Susanne E La Fleur, Johannes A Romijn, Max Nieuwdorp, Dongyan Zhang, Varman T SamuelAbstract:Summary Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic Diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic Diacylglycerols were strongly associated with hepatic PKCe activation, as reflected by PKCe translocation to the plasma membrane. These results demonstrate the relevance of hepatic Diacylglycerol-induced PKCe activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.
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cgi 58 knockdown sequesters Diacylglycerols in lipid droplets er preventing Diacylglycerol mediated hepatic insulin resistance
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jennifer L Cantley, Dongyan Zhang, Toru Yoshimura, Joao Paulo Camporez, Francois R Jornayvaz, Naoki Kumashiro, Fitsum Guebreegziabher, Michael J Jurczak, Mario Kahn, Blas A GuigniAbstract:Comparative gene identification 58 (CGI-58) is a lipid droplet-associated protein that promotes the hydrolysis of triglyceride by activating adipose triglyceride lipase. Loss-of-function mutations in CGI-58 in humans lead to Chanarin-Dorfman syndrome, a condition in which triglyceride accumulates in various tissues, including the skin, liver, muscle, and intestines. Therefore, without adequate CGI-58 expression, lipids are stored rather than used for fuel, signaling intermediates, and membrane biosynthesis. CGI-58 knockdown in mice using antisense oligonucleotide (ASO) treatment also leads to severe hepatic steatosis as well as increased hepatocellular Diacylglycerol (DAG) content, a well-documented trigger of insulin resistance. Surprisingly, CGI-58 knockdown mice remain insulin-sensitive, seemingly dissociating DAG from the development of insulin resistance. Therefore, we sought to determine the mechanism responsible for this paradox. Hyperinsulinemic-euglycemic clamp studies reveal that the maintenance of insulin sensitivity with CGI-58 ASO treatment could entirely be attributed to protection from lipid-induced hepatic insulin resistance, despite the apparent lipotoxic conditions. Analysis of the cellular compartmentation of DAG revealed that DAG increased in the membrane fraction of high fat-fed mice, leading to PKCe activation and hepatic insulin resistance. However, DAG increased in lipid droplets or lipid-associated endoplasmic reticulum rather than the membrane of CGI-58 ASO-treated mice, and thus prevented PKCe translocation to the plasma membrane and induction of insulin resistance. Taken together, these results explain the disassociation of hepatic steatosis and DAG accumulation from hepatic insulin resistance in CGI-58 ASO-treated mice, and highlight the importance of intracellular compartmentation of DAG in causing lipotoxicity and hepatic insulin resistance.
Christian Rosenmund - One of the best experts on this subject based on the ideXlab platform.
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move over protein kinase c you ve got company alternative cellular effectors of Diacylglycerol and phorbol esters
Journal of Cell Science, 2002Co-Authors: Nils Brose, Christian RosenmundAbstract:Diacylglycerol is an essential second messenger in mammalian cells. The most prominent intracellular targets of Diacylglycerol and of the functionally analogous phorbol esters belong to the protein kinase C (PKC) family. However, at least five alternative types of high-affinity Diacylglycerol/phorbol-ester receptor are known: chimaerins, protein kinase D, RasGRPs, Munc13s and DAG kinase γ. Recent evidence indicates that these have functional roles in Diacylglycerol second messenger signalling in vivo and that several cellular processes depend on these targets rather than protein kinase C isozymes. These findings contradict the still prevalent view according to which all Diacylglycerol/phorbol-ester effects are caused by the activation of protein kinase C isozymes. RasGRP1 (in Ras/Raf/MEK/ERK signalling) and Munc13-1 (in neurotransmitter secretion) are examples of non-PKC Diacylglycerol/phorbol-ester receptors that mediate Diacylglycerol and phorbol-ester effects originally thought to be caused by PKC isozymes. In the future, pharmacological studies on PKC must be complemented with alternative experimental approaches to allow the separation of PKC-mediated effects from those caused by alternative targets of the Diacylglycerol second messenger pathway. The examples of RasGRP1 and Munc13-1 show that detailed genetic analyses of C 1 -domain-containing non-PKC Diacylglycerol/phorbol-ester receptors in mammals are ideally suited to achieve this goal.
Blas A Guigni - One of the best experts on this subject based on the ideXlab platform.
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cgi 58 knockdown sequesters Diacylglycerols in lipid droplets er preventing Diacylglycerol mediated hepatic insulin resistance
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Jennifer L Cantley, Dongyan Zhang, Toru Yoshimura, Joao Paulo Camporez, Francois R Jornayvaz, Naoki Kumashiro, Fitsum Guebreegziabher, Michael J Jurczak, Mario Kahn, Blas A GuigniAbstract:Comparative gene identification 58 (CGI-58) is a lipid droplet-associated protein that promotes the hydrolysis of triglyceride by activating adipose triglyceride lipase. Loss-of-function mutations in CGI-58 in humans lead to Chanarin-Dorfman syndrome, a condition in which triglyceride accumulates in various tissues, including the skin, liver, muscle, and intestines. Therefore, without adequate CGI-58 expression, lipids are stored rather than used for fuel, signaling intermediates, and membrane biosynthesis. CGI-58 knockdown in mice using antisense oligonucleotide (ASO) treatment also leads to severe hepatic steatosis as well as increased hepatocellular Diacylglycerol (DAG) content, a well-documented trigger of insulin resistance. Surprisingly, CGI-58 knockdown mice remain insulin-sensitive, seemingly dissociating DAG from the development of insulin resistance. Therefore, we sought to determine the mechanism responsible for this paradox. Hyperinsulinemic-euglycemic clamp studies reveal that the maintenance of insulin sensitivity with CGI-58 ASO treatment could entirely be attributed to protection from lipid-induced hepatic insulin resistance, despite the apparent lipotoxic conditions. Analysis of the cellular compartmentation of DAG revealed that DAG increased in the membrane fraction of high fat-fed mice, leading to PKCe activation and hepatic insulin resistance. However, DAG increased in lipid droplets or lipid-associated endoplasmic reticulum rather than the membrane of CGI-58 ASO-treated mice, and thus prevented PKCe translocation to the plasma membrane and induction of insulin resistance. Taken together, these results explain the disassociation of hepatic steatosis and DAG accumulation from hepatic insulin resistance in CGI-58 ASO-treated mice, and highlight the importance of intracellular compartmentation of DAG in causing lipotoxicity and hepatic insulin resistance.
Kasper W Ter Horst - One of the best experts on this subject based on the ideXlab platform.
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hepatic Diacylglycerol associated protein kinase ce translocation links hepatic steatosis to hepatic insulin resistance in humans
Cell Reports, 2017Co-Authors: Kasper W Ter Horst, Pim W Gilijamse, Ruth I Versteeg, Mariette T Ackermans, Aart J Nederveen, Susanne E La Fleur, Johannes A Romijn, Max Nieuwdorp, Dongyan Zhang, Varman T SamuelAbstract:Summary Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic Diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic Diacylglycerols were strongly associated with hepatic PKCe activation, as reflected by PKCe translocation to the plasma membrane. These results demonstrate the relevance of hepatic Diacylglycerol-induced PKCe activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.