Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

Ryter, Stefan W.,Choi, Augustine M.K.,Kim, Hong Pyo Canadian Science Publishing 2014 Biochemistry and cell biology Vol.92 No.5

<P> Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1<SUP>−</SUP><SUP>/</SUP><SUP>−</SUP>) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1<SUP>−</SUP><SUP>/</SUP><SUP>−</SUP> fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1<SUP>−</SUP><SUP>/</SUP><SUP>−</SUP> liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis. </P>

Autophagy: A Critical Regulator of Cellular Metabolism and Homeostasis

Stefan W. Ryter,Suzanne M. Cloonan,Augustine M. K. Choi 한국분자세포생물학회 2013 Molecules and cells Vol.36 No.1

Autophagy is a dynamic process by which cytosolic mate-rial, including organelles, proteins, and pathogens, are sequestered into membrane vesicles called autopha-gosomes, and then delivered to the lysosome for degra-dation. By recycling cellular components, this process provides a mechanism for adaptation to starvation. The regulation of autophagy by nutrient signals involves a com- plex network of proteins that include mammalian target of rapamycin, the class III phosphatidylinositol-3 kinase/Be-clin 1 complex, and two ubiquitin-like conjugation systems. Additionally, autophagy, which can be induced by multiple forms of chemical and physical stress, including endo-plasmic reticulum stress, and hypoxia, plays an integral role in the mammalian stress response. Recent studies indicate that, in addition to bulk assimilation of cytosol, autophagy may proceed through selective pathways that target distinct cargoes to autophagosomes. The principle homeostatic functions of autophagy include the selective clearance of aggregated protein to preserve proteostasis, and the selective removal of dysfunctional mitochondria (mitophagy). Additionally, autophagy plays a central role in innate and adaptive immunity, with diverse functions such as regulation of inflammatory responses, antigen presen-tation, and pathogen clearance. Autophagy can preserve cellular function in a wide variety of tissue injury and disease states, however, maladaptive or pro-pathogenic outcomes have also been described. Among the many diseases where autophagy may play a role in-clude proteo-pathies which involve aberrant accumulation of proteins (e.g., neurodegenerative disorders), infectious diseases, and metabolic disorders such as diabetes and metabolic syndrome. Targeting the autophagy pathway and its regu-latory components may eventually lead to the develop-ment of therapeutics.

Carbon monoxide: present and future indications for a medical gas

Stefan W. Ryter,Augustine M. K. Choi 대한내과학회 2013 The Korean Journal of Internal Medicine Vol.28 No.2

Gaseous molecules continue to hold new promise in molecular medicine as experimental and clinical therapeutics. The low molecular weight gas carbon monoxide (CO), and similar gaseous molecules (e.g., H2S, nitric oxide) have been implicated as potential inhalation therapies in inf lammatory diseases. At high concentration, CO represents a toxic inhalation hazard, and is a common component of air pollution. CO is also produced endogenously as a product of heme degradation catalyzed by heme oxygenase enzymes. CO binds avidly to hemoglobin, causing hypoxemia and decreased oxygen delivery to tissues at high concentrations. At physiological concentrations, CO may have endogenous roles as a signal transduction molecule in the regulation of neural and vascular function and cellular homeostasis. CO has been demonstrated to act as an effective antiinf lammatory agent in preclinical animal models of inf lammation, acute lung injury, sepsis, ischemia/reperfusion injury, and organ transplantation. Additional experimental indications for this gas include pulmonary fibrosis, pulmonary hypertension, metabolic diseases, and preeclampsia. The development of chemical CO releasing compounds constitutes a novel pharmaceutical approach to CO delivery with demonstrated effectiveness in sepsis models. Current and pending clinical evaluation will determine the usefulness of this gas as a therapeutic in human disease.

FGF21 induced by carbon monoxide mediates metabolic homeostasis <i>via</i> the PERK/ATF4 pathway

Joe, Yeonsoo,Kim, Sena,Kim, Hyo Jeong,Park, Jeongmin,Chen, Yingqing,Park, Hyeok-Jun,Jekal, Seung-Joo,Ryter, Stefan W.,Kim, Uh Hyun,Chung, Hun Taeg Federation of American Societies for Experimental 2018 The FASEB Journal Vol. No.

<P>The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction <I>in vivo</I> and <I>in vitro</I>. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 <I>via</I> the eIF2α–ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.—Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis <I>via</I> the PERK/ATF4 pathway.</P>

Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases

Choi, Alexander J.S.,Ryter, Stefan W. Korean Society for Molecular and Cellular Biology 2014 Molecules and cells Vol.37 No.6

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multiprotein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-$1{\beta}$ and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-${\kappa}B$-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 ($P2X_7R$), which results in $K^+$ efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and /or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism

Park, Jeongmin,Joe, Yeonsoo,Ryter, Stefan W.,Surh, Young-Joon,Chung, Hun Taeg Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.4

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism

박정민,조연수,Stefan W. Ryter,서영준,정헌택 한국분자세포생물학회 2019 Molecules and cells Vol.42 No.4

Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert antiinflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.

CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes

Rah So-Young,Joe Yeonsoo,Park Jeongmin,Ryter Stefan W.,Park Chansu,Chung Hun Taeg,Kim Uh-Hyun 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD+ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca2+ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribose, which enhances the transcription of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase 1. These findings shed light on the role of nCD38 in glucagon-induced gluconeogenesis and provide insight into nuclear Ca2+ signals that mediate the transcription of key genes in gluconeogenesis under physiological conditions.

Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases

Alexander J.S. Choi,Stefan W. Ryter 한국분자세포생물학회 2014 Molecules and cells Vol.37 No.6

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multi-protein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-1 and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-B-dependent priming signal. Following exposure to extracel-lular ATP, stimulation of the P2X purinoreceptor-7 (P2X7R), which results in K+ efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and /or mitochondria-depen-dent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we dis-cuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer’s disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

Carbon monoxide, a reaction product of heme oxygenase-1, suppresses the expression of C-reactive protein by endoplasmic reticulum stress through modulation of the unfolded protein response

Chung, J.,Shin, D.Y.,Zheng, M.,Joe, Y.,Pae, H.O.,Ryter, S.W.,Chung, H.T. Pergamon Press 2011 Molecular immunology Vol.48 No.15

The expression of C-reactive protein (CRP) rises rapidly in response to inflammation. The endoplasmic reticulum (ER) stress has been reported to cause CRP expression. Carbon monoxide (CO), a reaction product of heme oxygenase, exerts anti-inflammatory effects. In this study, we aimed to examine the role of CO in modulating ER stress-induced CRP expression. In HepG2 cells, ER stress triggered by tunicamycin, thapsigargin and homocysteine markedly induced CRP expression and the activation of protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring transmembrane kinase/endonuclease 1α (IRE1α), activating transcription factor 6 (ATF6), and hepatocyte-specific cyclic AMP response element binding protein H (CREBH). A CO-releasing molecule (CORM) inhibited ER stress-induced CRP expression. While CORM attenuated ER stress-induced activation of IRE1α, ATF6 and CREBH, it augmented PERK activation, which was associated with its inhibition of CRP expression. CORM also inhibited CRP expression in response to the pro-inflammatory cytokine IL-6 that was found to induce ER stress response in HepG2 cells. Moreover, in mice treated with the ER stress inducer tunicamycin, CORM administration reduced serum levels of CRP and the expression of CRP mRNA in the liver. Collectively, our findings suggest that CO may attenuate ER stress-induced CRP expression through modulation of the unfolded protein response.