Type 2 diabetes is a metabolic, chronic disorder characterized by insulin resistance and elevated blood glucose levels. Although a large drug portfolio exists to keep the blood glucose levels under ...control, these medications are not without side effects. More importantly, once diagnosed diabetes is rarely reversible. Dysfunctions in the kidney, retina, cardiovascular system, neurons, and liver represent the common complications of diabetes, which again lack effective therapies that can reverse organ injury. Overall, the molecular mechanisms of how type 2 diabetes develops and leads to irreparable organ damage remain elusive. This review particularly focuses on novel targets that may play role in pathogenesis of type 2 diabetes. Further research on these targets may eventually pave the way to novel therapies for the treatment—or even the prevention—of type 2 diabetes along with its complications.
Type 2 diabetes is a complex metabolic disorder associated with a plethora of complications in peripheral organs. This review article highlights the novel targets that might play role in pathogenesis of type 2 diabetes. Further research on these targets might eventually pave the way to novel therapies for the treatment–or even the prevention–of type 2 diabetes.
•The GC/GR axis represents a major checkpoint in systemic stress responses and metabolic control.•Tissue-specific actions of the GR control essential components of glucose, lipid, bile acid and ...protein homeostasis.•Novel roles of the GC/GR axis comprise the regulation of the molecular clock and brain-periphery communication.
In the past decades, glucocorticoid (GC) hormones and their cognate, intracellular receptor, the glucocorticoid receptor (GR), have been well established as critical checkpoints in mammalian energy homeostasis. Whereas many aspects in healthy nutrient metabolism require physiological levels and/or action of GC, aberrant GC/GR signalling has been linked to severe metabolic dysfunction, including obesity, insulin resistance and type 2 diabetes. Consequently, studies of the molecular mechanisms within the GC signalling axis have become a major focus in biomedical research, up-to-date particularly focusing on systemic glucose and lipid handling. However, with the availability of novel high throughput technologies and more sophisticated metabolic phenotyping capabilities, as-yet non-appreciated, metabolic functions of GC have been recently discovered, including regulatory roles of the GC/GR axis in protein and bile acid homeostasis as well as metabolic inter-organ communication. Therefore, this review summarises recent advances in GC/GR biology, and summarises findings relevant for basic and translational metabolic research.
Secreted proteins constitute a large and biologically important subset of proteins that are involved in cellular communication, adhesion and migration. Yet secretomes are understudied because of ...technical limitations in the detection of low-abundance proteins against a background of serum-containing media. Here we introduce a method that combines click chemistry and pulsed stable isotope labeling with amino acids in cell culture to selectively enrich and quantify secreted proteins. The combination of these two labeling approaches allows cells to be studied irrespective of the complexity of the background proteins. We provide an in-depth and differential secretome analysis of various cell lines and primary cells, quantifying secreted factors, including cytokines, chemokines and growth factors. In addition, we reveal that serum starvation has a marked effect on secretome composition. We also analyze the kinetics of protein secretion by macrophages in response to lipopolysaccharides.
Advanced glycation end-products (AGEs) are non-enzymatic protein and amino acid adducts as well as DNA adducts which form from dicarbonyls and glucose. AGE formation is enhanced in diabetes and is ...associated with the development of diabetic complications. In the current review, we discuss mechanisms that lead to enhanced AGE levels in the context of diabetes and diabetic complications. The methylglyoxal-detoxifying glyoxalase system as well as alternative pathways of AGE detoxification are summarized. Therapeutic approaches to interfere with different pathways of AGE formation are presented.
The glyoxalase system is a highly specific enzyme system existing in all mammalian cells that is responsible for the detoxification of dicarbonyl species, primarily methylglyoxal (MG). It has been ...implicated to play an essential role in preventing the increased formation of advanced glycation end products under certain pathological conditions. We have established the first glyoxalase 1 knock-out model (GLO1
) in mammalian Schwann cells using the CRISPR/Cas9 technique to investigate compensatory mechanisms. Neither elevated concentrations of MG nor associated protein modifications were observed in GLO1
cells. Alternative detoxification of MG in GLO1
is achieved by increased catalytic efficiency of aldose reductase toward hemithioacetal (product of glutathione and MG), which is most likely caused by
-nitrosylation of aldose reductase. The hemithioacetal is mainly converted into lactaldehyde, which is paralleled by a loss of reduced glutathione. Inhibition of aldose reductase in GLO1
cells is associated with an increased sensitivity against MG, elevated intracellular MG levels, associated modifications, as well as increased oxidative stress. Our data suggest that aldose reductase can compensate for the loss of GLO1. This might be of clinical importance within the context of neuronal diseases caused by an impaired glyoxalase system and elevated levels of dicarbonyl species, such as MG.
Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign ...fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular “hub-centered” targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy.
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•Advanced NASH is accompanied by partial loss of hepatocyte identity•NASH-induced hepatokines associate with fibrosis-linked genes in hepatic stellate cells•A cooperative transcription factor network drives hepatocyte genomic reprogramming in NASH•Fibrosis-activated ELF3 and GLIS2 promote intra-hepatic crosstalk and liver fibrosis
The mechanisms that drive the advanced stages of metabolic-associated fatty liver disease (MALFD) are still largely unknown. Using a cell type-resolved genomics approach, Loft et al. identified a fibrosis-activated hepatocyte transcription factor network that contributes to the loss of hepatocyte identity and dictates intra-hepatic cross-talk during the progression of MALFD.
Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a ...critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function.
Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function. Wild-type mice were treated with neutralizing antibodies against the Notch ligand Delta-like 4. Fatty acid transport was studied in cultured endothelial cells and transgenic mice.
Treatment of wild-type mice with Delta-like 4 neutralizing antibodies for 8 weeks impaired fractional shortening and ejection fraction in the majority of mice. Inhibition of Notch signaling specifically in the endothelium of adult mice by genetic ablation of Rbp-jκ caused heart hypertrophy and failure. Impaired heart function was preceded by alterations in fatty acid metabolism and an increase in cardiac blood vessel density. Endothelial Notch signaling controlled the expression of endothelial lipase, Angptl4, CD36, and Fabp4, which are all needed for fatty acid transport across the vessel wall. In endothelial-specific Rbp-jκ-mutant mice, lipase activity and transendothelial transport of long-chain fatty acids to muscle cells were impaired. In turn, lipids accumulated in the plasma and liver. The attenuated supply of cardiomyocytes with long-chain fatty acids was accompanied by higher glucose uptake, increased concentration of glycolysis intermediates, and mTOR-S6K signaling. Treatment with the mTOR inhibitor rapamycin or displacing glucose as cardiac substrate by feeding a ketogenic diet prolonged the survival of endothelial-specific Rbp-jκ-deficient mice.
This study identifies Notch signaling as a novel regulator of fatty acid transport across the endothelium and as an essential repressor of angiogenesis in the adult heart. The data imply that the endothelium controls cardiomyocyte metabolism and function.
Obesity results from chronic energy surplus and excess lipid storage in white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) efficiently burns lipids through adaptive thermogenesis. ...Studying mouse models, we show that cyclooxygenase (COX)-2, a rate-limiting enzyme in prostaglandin (PG) synthesis, is a downstream effector of β-adrenergic signaling in WAT and is required for the induction of BAT in WAT depots. PG shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX-2 in WAT induced de novo BAT recruitment in WAT, increased systemic energy expenditure, and protected mice against high-fat diet-induced obesity. Thus, COX-2 appears integral to de novo BAT recruitment, which suggests that the PG pathway regulates systemic energy homeostasis.
p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic ...stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.
Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and ...fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a novel PPAR target gene and demonstrate its involvement in hepatic lipid metabolism. Microarray analysis revealed that Hilpda is one of the most highly induced genes by the PPARα agonist Wy14643 in mouse precision cut liver slices. Induction of Hilpda mRNA by Wy14643 was confirmed in mouse and human hepatocytes. Oral dosing with Wy14643 similarly induced Hilpda mRNA levels in livers of wild-type mice but not Ppara−/− mice. Transactivation studies and chromatin immunoprecipitation showed that Hilpda is a direct PPARα target gene via a conserved PPAR response element located 1200 base pairs upstream of the transcription start site. Hepatic overexpression of HILPDA in mice via adeno-associated virus led to a 4-fold increase in liver triglyceride storage, without any changes in key genes involved in de novo lipogenesis, β-oxidation, or lipolysis. Moreover, intracellular lipase activity was not affected by HILPDA overexpression. Strikingly, HILPDA overexpression significantly impaired hepatic triglyceride secretion. Taken together, our data uncover HILPDA as a novel PPAR target that raises hepatic triglyceride storage via regulation of triglyceride secretion.
Background: PPARα is an important regulator of hepatic lipid metabolism via target gene regulation.
Results: HILPDA is regulated by PPARα via an upstream PPRE. Targeted overexpression of HILPDA increases hepatic triglyceride storage via reduction of TG secretion.
Conclusion: HILPDA is a novel PPARα target involved in hepatic triglyceride secretion.
Significance: HILPDA might be a potential target in the treatment of non-alcoholic fatty liver disease.
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