The Experts below are selected from a list of 2481 Experts worldwide ranked by ideXlab platform
Louis Ragolia - One of the best experts on this subject based on the ideXlab platform.
-
lipocalin type Prostaglandin D2 Synthase appears to function as a novel adipokine preventing adipose dysfunction in response to a high fat diet
Prostaglandins & Other Lipid Mediators, 2021Co-Authors: Ankita Srivastava, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Adipose dysfunction is the primary defect in obesity that contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and some cancers. Previously, we demonstrated the development of NAFLD in lipocalin-type Prostaglandin D2 Synthase (L-PGDS) knockout mice regardless of diet. In the present study, we examined the role of L-PGDS in adipose in response to a high fat diet. We observed decreased expression of L-PGDS in adipose tissue and concomitant lower plasma levels in a dietary model of obesity as well as in insulin resistant 3T3-L1 adipocytes. We show reduced adiponectin expression and phosphorylation of AMPK in white adipose tissue of L-PGDS KO mice after 14 weeks on a high fat diet as compared to control C57BL/6 mice. We also observe an increased fat content in L-PGDS KO mice as demonstrated by adipocyte hypertrophy and increased expression of lipogenenic genes. We confirmed our in vivo findings in in vitro 3T3-L1 adipocytes, using an enzymatic inhibitor of L-PGDS (AT56). Rosiglitazone treatment drastically increased L-PGDS expression in insulin resistant 3T3-L1 adipocytes and increased adiponectin expression and AMPK phosphorylation in AT56 treated 3T3-L1 adipocytes. We conclude that the absence of L-PGDS has a deleterious effect on adipose tissue functioning, which further reduces insulin sensitivity in adipose tissue. Consequently, we propose L-PGDS appears to function as a potential member of the adipokine secretome involved in the regulation of the obesity-associated metabolic syndrome.
-
116 or lipocalin type Prostaglandin D2 Synthase depletion induces adipose tissue dysfunction in response to high fat diet
Diabetes, 2021Co-Authors: Ankita Srivastava, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Adipose tissue dysfunction is the primary defect in obesity which contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease and some cancers. Previous study from our lab implicated the role of lipocalin-type Prostaglandin D2 Synthase (L-PGDS) in glucose intolerance and atherosclerosis. Our lab also showed the development of NAFLD in L-PGDS knockout mice on both low fat and high fat diet. In the present study, we examined the role of L-PGDS in adipose tissue in response to high fat diet. We found decreased expression of L-PGDS in visceral and subcutaneous white adipose tissue (WAT) of C57BL/6 mice after 12 weeks on high fat diet (HFD). Our study showed increased fat content in L-PGDS KO mice as compared to control C57BL/6 mice after 14 weeks on HFD. Histological analysis showed hypertrophied adipocytes in visceral WAT of L-PGDS KO mice as compared to control mice. Furthermore, we found increased expression of the lipogenesis genes LXRα, SREBP-1c and FAS in visceral WAT of L-PGDS KO mice after 14 weeks on HFD. L-PGDS KO mice showed reduced gene expression of adiponectin and PPARγ in visceral WAT on HFD. The plasma adiponectin level was also decreased in L-PGDS KO mice. We conclude that absence of L-PGDS has a deleterious effect on adipose tissue functioning which further reduces insulin sensitivity in adipose tissue. Thus, our study suggests L-PGDS as a novel therapeutic target for the treatment of obesity-associated metabolic syndrome. Disclosure A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None. Funding American Heart Association (15GRNT22420001); George Link, Jr. Foundation Inc. (3500-7294)
-
1890 p lipocalin type Prostaglandin D2 Synthase deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease independent of obesity
Diabetes, 2019Co-Authors: Ankita Srivastava, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Nonalcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease, and all-cause mortality. Obesity is a major determinant of the high prevalence of NAFLD and T2DM worldwide. Previously, we demonstrated that lipocalin-type Prostaglandin D 2 Synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in causing NAFLD in L-PGDS knockout (KO) and control C57BL/6 mice (n=6/group) on both low fat and high fat diets for 14 weeks. We observed that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster, even on the low fat diet. In addition, we found elevated fasting glucose and insulin levels in L-PGDS KO mice with increased lipid accumulation in the liver with time on both diets as compared to controls. We also found total cholesterol and LDL levels were significantly elevated in L-PGDS KO mice. Finally, lipogenesis marker proteins such as SREBP-1c and LXRα, and CD36, a fatty acid transporter protein, were also found to be increased in L-PGDS KO mice on both diets as compared to control mice. These data confirm that absence of L-PGDS results in hyperinsulinemia and dyslipidemia. Therefore, we conclude that L-PGDS plays a significant role in developing NAFLD independent of obesity and may serve as a novel therapeutic target for the treatment of NAFLD. Disclosure A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None. Funding George Link, Jr. Foundation, Inc.; American Heart Association
-
lipocalin Prostaglandin D2 Synthase lpgds levels following sleeve gastrectomy and a very low calorie diet vlcd a pilot study
Diabetes, 2018Co-Authors: Raymond Lau, Thomas Palaia, Sunil Kumar, Shahidul Islam, Jenny J Lee, Christopher J Hall, Collin E Brathwaite, Louis RagoliaAbstract:Background: Lipocalin Prostaglandin D2 Synthase (LPGDS) is a bile acid binding protein that has been found to have a significant role in glucose metabolism and appetite. In performing sleeve gastrectomy (SG) and gastric bypass in rodent models, we have also demonstrated LPGDS appears to have an important role in the beneficial metabolic effects seen after surgery. We have sought to correlate if LPGDS has a significant clinical effect in humans for surgical weight loss. Methods: Serum LPGDS levels were obtained in patients undergoing SG before, and then one month following surgery. Serum LPGDS was also measured in subjects undergoing a very low calorie diet (VLCD) program before, and then one month following the start of the program. LPGDS levels were measured by ELISA and analyzed. Results: Subjects that underwent surgical loss went from 304.45 +/-74 pounds before surgery to 271.4 +/- 70 pounds one month following surgery. Subjects that underwent VLCD went from 273.1 +/- 65 pounds before the program to 255 +/-61 pounds one month after starting the program. LPGDS levels for surgical weight loss increased from 579.9 +/-161 ng/mL before the program to 694.6 +/- 448 ng/mL one month after surgery. LPGDS for VLCD was 583.1 +/- 187 ng/mL before the program and 598.4 +/- 165 ng/mL one month after starting the program. Conclusion: LPGDS levels appear to increase after sleeve gastrectomy but not VLCD, although this trend is not statistically significant. Further study is needed to confirm this trend. Disclosure R.G. Lau: None. S. Kumar: None. J. Lee: None. T. Palaia: None. S. Islam: None. C. Brathwaite: None. L. Ragolia: None.
-
lipocalin type Prostaglandin D2 Synthase l pgds knockout mice exhibits hepatosteatosis mediated by enhanced cd36 hepatic expression as a result of hyperinsulinemia
Diabetes, 2018Co-Authors: Sunil Kumar, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Hepatosteatosis is strongly associated with hyperinsulinaemia and obesity. Previously, we demonstrated accelerated atherosclerosis and impaired glucose tolerance in L-PGDS knockout (KO) mice. Interestingly, L-PGDS KO mice also exhibit hyperinsulinemia on high fat diet in a time-dependent manner. In this study, we investigated the role of L-PGDS on liver pathophysiology using L-PGDS KO mice compared to control C57BL/6 mice) (n=6/group). Mice were kept on high fat diet (60% fat) for 14 weeks and all parameters were measured initially and at 4-, 8- and 14-weeks post high fat diet. Data were analyzed by unpaired t-test or one-way ANOVA where appropriate with p Disclosure S. Kumar: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.
Thomas Palaia - One of the best experts on this subject based on the ideXlab platform.
-
lipocalin type Prostaglandin D2 Synthase appears to function as a novel adipokine preventing adipose dysfunction in response to a high fat diet
Prostaglandins & Other Lipid Mediators, 2021Co-Authors: Ankita Srivastava, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Adipose dysfunction is the primary defect in obesity that contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and some cancers. Previously, we demonstrated the development of NAFLD in lipocalin-type Prostaglandin D2 Synthase (L-PGDS) knockout mice regardless of diet. In the present study, we examined the role of L-PGDS in adipose in response to a high fat diet. We observed decreased expression of L-PGDS in adipose tissue and concomitant lower plasma levels in a dietary model of obesity as well as in insulin resistant 3T3-L1 adipocytes. We show reduced adiponectin expression and phosphorylation of AMPK in white adipose tissue of L-PGDS KO mice after 14 weeks on a high fat diet as compared to control C57BL/6 mice. We also observe an increased fat content in L-PGDS KO mice as demonstrated by adipocyte hypertrophy and increased expression of lipogenenic genes. We confirmed our in vivo findings in in vitro 3T3-L1 adipocytes, using an enzymatic inhibitor of L-PGDS (AT56). Rosiglitazone treatment drastically increased L-PGDS expression in insulin resistant 3T3-L1 adipocytes and increased adiponectin expression and AMPK phosphorylation in AT56 treated 3T3-L1 adipocytes. We conclude that the absence of L-PGDS has a deleterious effect on adipose tissue functioning, which further reduces insulin sensitivity in adipose tissue. Consequently, we propose L-PGDS appears to function as a potential member of the adipokine secretome involved in the regulation of the obesity-associated metabolic syndrome.
-
116 or lipocalin type Prostaglandin D2 Synthase depletion induces adipose tissue dysfunction in response to high fat diet
Diabetes, 2021Co-Authors: Ankita Srivastava, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Adipose tissue dysfunction is the primary defect in obesity which contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, nonalcoholic fatty liver disease and some cancers. Previous study from our lab implicated the role of lipocalin-type Prostaglandin D2 Synthase (L-PGDS) in glucose intolerance and atherosclerosis. Our lab also showed the development of NAFLD in L-PGDS knockout mice on both low fat and high fat diet. In the present study, we examined the role of L-PGDS in adipose tissue in response to high fat diet. We found decreased expression of L-PGDS in visceral and subcutaneous white adipose tissue (WAT) of C57BL/6 mice after 12 weeks on high fat diet (HFD). Our study showed increased fat content in L-PGDS KO mice as compared to control C57BL/6 mice after 14 weeks on HFD. Histological analysis showed hypertrophied adipocytes in visceral WAT of L-PGDS KO mice as compared to control mice. Furthermore, we found increased expression of the lipogenesis genes LXRα, SREBP-1c and FAS in visceral WAT of L-PGDS KO mice after 14 weeks on HFD. L-PGDS KO mice showed reduced gene expression of adiponectin and PPARγ in visceral WAT on HFD. The plasma adiponectin level was also decreased in L-PGDS KO mice. We conclude that absence of L-PGDS has a deleterious effect on adipose tissue functioning which further reduces insulin sensitivity in adipose tissue. Thus, our study suggests L-PGDS as a novel therapeutic target for the treatment of obesity-associated metabolic syndrome. Disclosure A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None. Funding American Heart Association (15GRNT22420001); George Link, Jr. Foundation Inc. (3500-7294)
-
1890 p lipocalin type Prostaglandin D2 Synthase deficient mice develop dyslipidemia resulting in nonalcoholic fatty liver disease independent of obesity
Diabetes, 2019Co-Authors: Ankita Srivastava, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Nonalcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus (T2DM), cardiovascular disease, and all-cause mortality. Obesity is a major determinant of the high prevalence of NAFLD and T2DM worldwide. Previously, we demonstrated that lipocalin-type Prostaglandin D 2 Synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in causing NAFLD in L-PGDS knockout (KO) and control C57BL/6 mice (n=6/group) on both low fat and high fat diets for 14 weeks. We observed that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster, even on the low fat diet. In addition, we found elevated fasting glucose and insulin levels in L-PGDS KO mice with increased lipid accumulation in the liver with time on both diets as compared to controls. We also found total cholesterol and LDL levels were significantly elevated in L-PGDS KO mice. Finally, lipogenesis marker proteins such as SREBP-1c and LXRα, and CD36, a fatty acid transporter protein, were also found to be increased in L-PGDS KO mice on both diets as compared to control mice. These data confirm that absence of L-PGDS results in hyperinsulinemia and dyslipidemia. Therefore, we conclude that L-PGDS plays a significant role in developing NAFLD independent of obesity and may serve as a novel therapeutic target for the treatment of NAFLD. Disclosure A. Srivastava: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None. Funding George Link, Jr. Foundation, Inc.; American Heart Association
-
lipocalin Prostaglandin D2 Synthase lpgds levels following sleeve gastrectomy and a very low calorie diet vlcd a pilot study
Diabetes, 2018Co-Authors: Raymond Lau, Thomas Palaia, Sunil Kumar, Shahidul Islam, Jenny J Lee, Christopher J Hall, Collin E Brathwaite, Louis RagoliaAbstract:Background: Lipocalin Prostaglandin D2 Synthase (LPGDS) is a bile acid binding protein that has been found to have a significant role in glucose metabolism and appetite. In performing sleeve gastrectomy (SG) and gastric bypass in rodent models, we have also demonstrated LPGDS appears to have an important role in the beneficial metabolic effects seen after surgery. We have sought to correlate if LPGDS has a significant clinical effect in humans for surgical weight loss. Methods: Serum LPGDS levels were obtained in patients undergoing SG before, and then one month following surgery. Serum LPGDS was also measured in subjects undergoing a very low calorie diet (VLCD) program before, and then one month following the start of the program. LPGDS levels were measured by ELISA and analyzed. Results: Subjects that underwent surgical loss went from 304.45 +/-74 pounds before surgery to 271.4 +/- 70 pounds one month following surgery. Subjects that underwent VLCD went from 273.1 +/- 65 pounds before the program to 255 +/-61 pounds one month after starting the program. LPGDS levels for surgical weight loss increased from 579.9 +/-161 ng/mL before the program to 694.6 +/- 448 ng/mL one month after surgery. LPGDS for VLCD was 583.1 +/- 187 ng/mL before the program and 598.4 +/- 165 ng/mL one month after starting the program. Conclusion: LPGDS levels appear to increase after sleeve gastrectomy but not VLCD, although this trend is not statistically significant. Further study is needed to confirm this trend. Disclosure R.G. Lau: None. S. Kumar: None. J. Lee: None. T. Palaia: None. S. Islam: None. C. Brathwaite: None. L. Ragolia: None.
-
lipocalin type Prostaglandin D2 Synthase l pgds knockout mice exhibits hepatosteatosis mediated by enhanced cd36 hepatic expression as a result of hyperinsulinemia
Diabetes, 2018Co-Authors: Sunil Kumar, Thomas Palaia, Jenny J Lee, Christopher J Hall, Matthew Stevenson, Louis RagoliaAbstract:Hepatosteatosis is strongly associated with hyperinsulinaemia and obesity. Previously, we demonstrated accelerated atherosclerosis and impaired glucose tolerance in L-PGDS knockout (KO) mice. Interestingly, L-PGDS KO mice also exhibit hyperinsulinemia on high fat diet in a time-dependent manner. In this study, we investigated the role of L-PGDS on liver pathophysiology using L-PGDS KO mice compared to control C57BL/6 mice) (n=6/group). Mice were kept on high fat diet (60% fat) for 14 weeks and all parameters were measured initially and at 4-, 8- and 14-weeks post high fat diet. Data were analyzed by unpaired t-test or one-way ANOVA where appropriate with p Disclosure S. Kumar: None. T. Palaia: None. C. Hall: None. J. Lee: None. M. Stevenson: None. L. Ragolia: None.
John K Maesaka - One of the best experts on this subject based on the ideXlab platform.
-
Prostaglandin D2 Synthase apoptotic factor in alzheimer plasma inducer of reactive oxygen species inflammatory cytokines and dialysis dementia
Journal of nephropathology, 2013Co-Authors: John K Maesaka, Thomas Palaia, Louis Ragolia, Bali Sodam, Vecihi Batuman, Nobuyuki Miyawaki, Shubha Shastry, Steven Youmans, Marwan ElsabbanAbstract:Background: Apoptosis, reactive oxygen species (ROS) and inflammatory cytokines have all been implicated in the development of Alzheimer’s disease (AD). Objectives: The present study identifies the apoptotic factor that was responsible for the fourfold increase in apoptotic rates that we previously noted when pig proximal tubule, LLC-PK1, cells were exposed to AD plasma as compared to plasma from normal controls and multi-infarct dementia. Patients and Methods: The apoptotic factor was isolated from AD urine and identified as lipocalin-type Prostaglandin D2 Synthase (L-PGDS). L-PGDS was found to be the major apoptotic factor in AD plasma as determined by inhibition of apoptosis approximating control levels by the cyclo-oxygenase (COX) 2 inhibitor, NS398, and the antibody to L-PGDS. Blood levels of L-PGDS, however, were not elevated in AD. We now demonstrate a receptor-mediated uptake of L-PGDS in PC12 neuronal cells that was time, dose and temperature-dependent and was saturable by competition with cold L-PGDS and albumin. Further proof of this endocytosis was provided by an electron microscopic study of gold labeled L-PGDS and immunofluorescence with Alexa-labeled L-PGDS. Results: The recombinant L-PGDS and wild type (WT) L-PGDS increased ROS but only the WTL-PGDS increased IL6 and TNFα, suggesting that differences in glycosylation of L-PGDS in AD was responsible for this discrepancy. Conclusions: These data collectively suggest that L-PGDS might play an important role in the development of dementia in patients on dialysis and of AD.
-
accelerated glucose intolerance nephropathy and atherosclerosis in Prostaglandin D2 Synthase knock out mice
Journal of Biological Chemistry, 2005Co-Authors: Louis Ragolia, Thomas Palaia, Christopher E Hall, John K Maesaka, Naomi Eguchi, Yoshihiro UradeAbstract:Abstract Type 2 diabetics have an increased risk of developing atherosclerosis, suggesting the mechanisms that cause this disease are enhanced by insulin resistance. In this study we examined the effects of gene knock-out (KO) of lipocalin-type Prostaglandin D2 Synthase (L-PGDS), a protein found at elevated levels in type 2 diabetics, on diet-induced glucose tolerance and atherosclerosis. Our results show that L-PGDS KO mice become glucose-in-tolerant and insulin-resistant at an accelerated rate when compared with the C57BL/6 control strain. Adipocytes were significantly larger in the L-PGDS KO mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls. In addition, only the L-PGDS KO mice developed nephropathy and an aortic thickening reminiscent to the early stages of atherosclerosis when fed a “diabetogenic” high fat diet. We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy.
-
inhibition of cell cycle progression and migration of vascular smooth muscle cells by Prostaglandin D2 Synthase resistance in diabetic goto kakizaki rats
American Journal of Physiology-cell Physiology, 2004Co-Authors: Louis Ragolia, Thomas Palaia, Tara B Koutrouby, John K MaesakaAbstract:The regulation of vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis plays a clear role in the atherosclerotic process. Recently, we reported on the inhibition of the exagge...
-
Prostaglandin D2 Synthase inhibits the exaggerated growth phenotype of spontaneously hypertensive rat vascular smooth muscle cells
Journal of Biological Chemistry, 2003Co-Authors: Louis Ragolia, Thomas Palaia, John K Maesaka, Enesa ParicAbstract:Lipocalin-type Prostaglandin D2 Synthase (L-PGDS) has recently been linked to a variety of pathophysiological cardiovascular conditions including hypertension and diabetes. In this study, we report on the 50% increase in L-PGDS protein expression observed in vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR). L-PGDS expression also increased 50% upon the differentiation of normotensive control cells (WKY, from Wistar-Kyoto rats). In addition, we demonstrate differential effects of L-PGDS treatment on cell proliferation and apoptosis in VSMCs isolated from SHR versus WKY controls. L-PGDS (50 microg/ml) was able to significantly inhibit VSMC proliferation and DNA synthesis and induce the apoptotic genes bax, bcl-x, and ei24 in SHR but had no effect on WKY cells. Hyperglycemic conditions also had opposite effects, in which increased glucose concentrations (20 mm) resulted in decreased L-PGDS expression in control cells but actually stimulated L-PGDS expression in SHR. Furthermore, we examined the effect of L-PGDS incubation on insulin-stimulated Akt, glycogen Synthase kinase-3beta (GSK-3beta), and ERK phosphorylation. Unexpectedly, we found that when WKY cells were pretreated with L-PGDS, insulin could actually induce apoptosis and failed to stimulate Akt/GSK-3beta phosphorylation. Insulin-stimulated ERK phosphorylation was unaffected by L-PGDS pretreatment in both cell lines. We propose that L-PGDS is involved in the balance of VSMC proliferation and apoptosis and in the increased expression observed in the hypertensive state is an attempt to maintain a proper equilibrium between the two processes via the induction of apoptosis and inhibition of cell proliferation.
-
elevated l pgds activity contributes to pma induced apoptosis concomitant with downregulation of pi3 k
American Journal of Physiology-cell Physiology, 2003Co-Authors: Thomas Palaia, Louis Ragolia, John K Maesaka, Enesa ParicAbstract:Recently we demonstrated the induction of apoptosis by the addition of recombinant lipocalin-type Prostaglandin D2 Synthase (L-PGDS) to the culture medium of LLC-PK1 cells. Because protein kinase C...
Luis A Garza - One of the best experts on this subject based on the ideXlab platform.
-
does Prostaglandin D2 hold the cure to male pattern baldness
Experimental Dermatology, 2014Co-Authors: Ashley Nieves, Luis A GarzaAbstract:Lipids in the skin are the most diverse in the entire human body. Their bioactivity in health and disease is underexplored. Prostaglandin D2 has recently been identified as a factor which is elevated in the bald scalp of men with androgenetic alopecia (AGA) and has the capacity to decrease hair lengthening. An enzyme which synthesizes it, Prostaglandin D2 Synthase (PTGDS or lipocalin-PGDS), is hormone responsive in multiple other organs. PGD2 has two known receptors, GPR44 and PTGDR. GPR44 was found to be necessary for the decrease in hair growth by PGD2. This creates an exciting opportunity to perhaps create novel treatments for AGA, which inhibit the activity of PTGDS, PGD2 or GPR44. This review discusses the current knowledge surrounding PGD2, and future steps needed to translate these findings into novel therapies for patients with AGA.
-
Prostaglandin D2 inhibits wound induced hair follicle neogenesis through the receptor gpr44
Journal of Investigative Dermatology, 2013Co-Authors: Amanda M Nelson, John A Lawson, Dorothy E Loy, Adiya S Katseff, Garret A Fitzgerald, Luis A GarzaAbstract:Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late, respectively, during wound healing. The levels of WIHN, lipocalin-type Prostaglandin D2 Synthase (Ptgds), and its product PGD2 each varied significantly among background strains of mice after wounding, and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. In addition, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild-type mice, and PGD2 receptor Gpr44-null mice showed increased WIHN compared with strain-matched control mice. Furthermore, Gpr44-null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration.
-
Prostaglandin D2 inhibits wound induced hair follicle neogenesis through the receptor gpr44
Journal of Investigative Dermatology, 2013Co-Authors: Amanda M Nelson, John A Lawson, Adiya S Katseff, Garret A Fitzgerald, Luis A GarzaAbstract:Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late, respectively, during wound healing. The levels of WIHN, lipocalin-type Prostaglandin D2 Synthase (Ptgds), and its product PGD2 each varied significantly among background strains of mice after wounding, and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. In addition, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild-type mice, and PGD2 receptor Gpr44-null mice showed increased WIHN compared with strain-matched control mice. Furthermore, Gpr44-null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration.
-
Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia
Science Translational Medicine, 2012Co-Authors: Luis A Garza, Zaixin Yang, Brinda Alagesan, John A Lawson, Scott M Norberg, Tailun Zhao, Hanz Blatt, David C Stanton, Lee Carrasco, Gurpreet AhluwaliaAbstract:Testosterone is necessary for the development of male pattern baldness, known as androgenetic alopecia (AGA); yet, the mechanisms for decreased hair growth in this disorder are unclear. We show that Prostaglandin D2 Synthase (PTGDS) is elevated at the mRNA and protein levels in bald scalp compared to haired scalp of men with AGA. The product of PTGDS enzyme activity, Prostaglandin D2 (PGD2), is similarly elevated in bald scalp. During normal follicle cycling in mice, Ptgds and PGD2 levels increase immediately preceding the regression phase, suggesting an inhibitory effect on hair growth. We show that PGD2 inhibits hair growth in explanted human hair follicles and when applied topically to mice. Hair growth inhibition requires the PGD2 receptor G protein (heterotrimeric guanine nucleotide)–coupled receptor 44 (GPR44), but not the PGD2 receptor 1 (PTGDR). Furthermore, we find that a transgenic mouse, K14-Ptgs2, which targets Prostaglandin-endoperoxide Synthase 2 expression to the skin, demonstrates elevated levels of PGD2 in the skin and develops alopecia, follicular miniaturization, and sebaceous gland hyperplasia, which are all hallmarks of human AGA. These results define PGD2 as an inhibitor of hair growth in AGA and suggest the PGD2-GPR44 pathway as a potential target for treatment.
Yoshihiro Urade - One of the best experts on this subject based on the ideXlab platform.
-
biochemical and structural characteristics gene regulation physiological pathological and clinical features of lipocalin type Prostaglandin D2 Synthase as a multifunctional lipocalin
Frontiers in Physiology, 2021Co-Authors: Yoshihiro UradeAbstract:Lipocalin-type Prostaglandin (PG) D2 Synthase (L-PGDS) catalyzes the isomerization of PGH2, a common precursor of the two series of PGs, to produce PGD2. PGD2 stimulates three distinct types of G protein-coupled receptors: (1) D type of prostanoid (DP) receptors involved in the regulation of sleep, pain, food intake, and others; (2) chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) receptors, in myelination of peripheral nervous system, adipocyte differentiation, inhibition of hair follicle neogenesis, and others; and (3) F type of prostanoid (FP) receptors, in dexamethasone-induced cardioprotection. L-PGDS is the same protein as β-trace, a major protein in human cerebrospinal fluid (CSF). L-PGDS exists in the central nervous system and male genital organs of various mammals, and human heart; and is secreted into the CSF, seminal plasma, and plasma, respectively. L-PGDS binds retinoic acids and retinal with high affinities (Kd < 100 nM) and diverse small lipophilic substances, such as thyroids, gangliosides, bilirubin and biliverdin, heme, NAD(P)H, and PGD2, acting as an extracellular carrier of these substances. L-PGDS also binds amyloid β peptides, prevents their fibril formation, and disaggregates amyloid β fibrils, acting as a major amyloid β chaperone in human CSF. Here, I summarize the recent progress of the research on PGD2 and L-PGDS, in terms of its "molecular properties," "cell culture studies," "animal experiments," and "clinical studies," all of which should help to understand the pathophysiological role of L-PGDS and inspire the future research of this multifunctional lipocalin.
-
abstract 16443 therapeutic effect of Prostaglandin D2 Synthase inhibition in experimental autoimmune myocarditis
Circulation, 2016Co-Authors: Toshihiro Yamaguchi, Yoshihiro Urade, Yoshihiro Motozawa, Hidetoshi Kumagai, Masakazu Shinohara, Yuichi Ikeda, Ichiro Manabe, Kosuke Aritake, Issei KomuroAbstract:Introduction: Myocarditis is a life-threatening inflammatory cardiac disorder. Virus-triggered autoimmunity is considered to play a key role in the progression of myocarditis, however, detailed mol...
-
Prostaglandin D2 Synthase gpr44 a signaling axis in pns myelination
Nature Neuroscience, 2014Co-Authors: Amelia Trimarco, Maria Grazia Forese, Valentina Alfieri, Alessandra Lucente, P G Brambilla, Giorgia Dina, Damiana Pieragostino, Paolo Sacchetta, Yoshihiro Urade, Brigitte BoizetbonhoureAbstract:Neuregulin 1 (NRG1) type III is a key mediator of Schwann cell development and myelination and is known to undergo proteolytic cleavage to produce an intracellular fragment. In this study, the authors show that this intracellular fragment of NRG1 modulates myelination by inducing the expression of a Prostaglandin Synthase (L-PGDS) which, in turn, leads to Prostaglandin production and activation of GPR44.
-
Prostaglandin D2 Synthase gpr44 a signaling axis in pns myelination
Nature Neuroscience, 2014Co-Authors: Amelia Trimarco, Maria Grazia Forese, Valentina Alfieri, Alessandra Lucente, P G Brambilla, Giorgia Dina, Damiana Pieragostino, Paolo Sacchetta, Yoshihiro Urade, Brigitte BoizetbonhoureAbstract:Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of neuregulin 1 type III upregulated the Prostaglandin D2 Synthase (L-pgds, also known as Ptgds) gene, which, together with the G protein-coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.
-
the lipocalin type Prostaglandin D2 Synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic pituitary adrenal axis hyperactivity
Journal of Endocrinology, 2013Co-Authors: Jodi F Evans, Naomi Eguchi, Yoshihiro Urade, Shahidul Islam, Louis RagoliaAbstract:Obesity and diabetes are closely associated with hyperactivation of the hypothalamic– pituitary–adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type Prostaglandin D2 Synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.
