scholarly journals Gemfibrozil Induces Anemia, Leukopenia and Reduces Hematopoietic Stem Cells via PPAR-α in Mice

2020 ◽  
Vol 21 (14) ◽  
pp. 5050
Author(s):  
Gabriel Rufino Estrela ◽  
Adriano Cleis Arruda ◽  
Heron Fernandes Vieira Torquato ◽  
Leandro Ceotto Freitas-Lima ◽  
Mauro Sérgio Perilhão ◽  
...  
Keyword(s):  
Stem Cells ◽  
Knockout Mice ◽  
Blood Cells ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Ppar Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hematopoietic Stem ◽  
Receptor Alpha

Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha (HIF-2α) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice.

Sparc Is Dispensable for Murine Hematopoiesis, Despite Its Suspected Role in 5q- Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4822-4822
Author(s):  
Kavitha Siva ◽  
Pekka Jaako ◽  
Kenichi Miharada ◽  
Emma Rörby ◽  
Mats Ehinger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Knockout Mice ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Lethal Dose ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Normal Peripheral Blood ◽  
Expression Levels

Abstract Abstract 4822 Hematopoiesis is a complex process where a limited number of stem cells give rise to all mature blood cells. It involves interplay of several factors, many of which are yet to be identified. In a search for novel regulators of hematopoiesis, we chose to study SPARC (Secreted Protein Acidic and Rich in Cysteine, also known as Osteonection and BM40) because it is downregulated upon hematopoietic differentiation (Bruno et al., Mol Cell Biol, 2004) and might therefore play a role in the regulation of hematopoietic stem cells (HSC). SPARC is a matricellular protein that forms a major component of bone and is ubiquitously expressed in a variety of tissues. It is the founding member of a family of SPARC-like proteins. Several publications have indicated an important role for SPARC in hematopoiesis. In particular – knockdown of SPARC in zebrafish embryos resulted in an altered number of circulating blood cells, and a knockout mouse model showed thrombocytopenia and reduced erythroid colony formation. We carried out an in depth phenotypic and functional analysis of the hematopoietic system of SPARC knockout mice; using it as a model to gain insight into the role of SPARC in hematopoiesis. These mice are viable and fertile but show severe osteopenia and age-onset cataract at about six months of age. They also show an altered response to tumour growth and wound healing. We used mice (129SVJ background) (Gilmour et al. EMBO, 1998) that were less than six months old. These mice had normal peripheral blood counts and the bone marrow and spleen showed no alterations in morphology or cellularity. A detailed phenotypic analysis of precursors within the bone marrow showed no significant differences in myelo-erythroid precursors as compared to wild types (n=6). Though in vitro, the precursors showed lower ability to form BFU-E (n=5, p=0.048). In transplantations of lethally irradiated recipient mice, SPARC knockout cells gave rise to multi-lineage long-term reconstitution. Also, when competed with wild type cells, they provided reconstitution as well as their wild type counterparts. When SPARC knockout mice (n=8) were transplanted with wild type cells, there was normal reconstitution, indicating that a SPARC deficient niche can fully support normal hematopoiesis. We also tested if SPARC deficient mice respond differently to hematopoietic stress. We subjected mice (n=7) to sub lethal dose of irradiation and to experimentally induced anemia (n=7) and followed recovery by analyzing peripheral blood counts. In both SPARC knockouts and wild type mice, the blood counts recovered in a similar fashion. In conclusion, we find that SPARC is dispensable for murine hematopoiesis. It is possible that there are compensatory mechanisms involving other members of the SPARC family that ultimately lead to normal hematopoiesis in the murine model. In humans, SPARC maps to the deleted region in 5q MDS and has been reported to be 71 % down regulated in patient samples (Lehmann et al. Leukemia, 2007). It is the most prominent gene that is up regulated in response to lenalidomide, a drug that inhibits the malignant clone (Pellagatti et al. PNAS, 2007). SPARC is thus increasingly speculated to be involved in the pathophysiology of this hematopoetic disease. We analysed the expression levels of SPARC mRNA in the hematopoietic stem/progenitor cell compartment and found high expression levels in the CD34+ fraction of human cord blood cells. In contrast, there is very low level of SPARC expression in all compartments of murine HSCs. Therefore SPARC function may play a more important role in human hematopoiesis than in murine blood cell regulation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals EFFECT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA-AGONISTS ON DIABETES-INDUCED ACUTE KIDNEY INJURY: ROLE OF OXIDATIVE STRESS AND HYPERLIPIDEMIA

2019 ◽  
Vol 12 (1) ◽  
pp. 143
Author(s):  
Vishal Arvind Chakkarwar ◽  
Pravin Kawtikwar
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Single Dose ◽  
Lipid Profile ◽  
Density Lipoprotein ◽  
Kidney Injury ◽  
Diabetic Rats ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha

Objective: The present study investigated the possible effect of fenofibrate and gemfibrozil peroxisome proliferator-activated receptor-alpha agonist in diabetes-induced acute kidney injury (AKI) in rats.Methods: Rats were administered streptozotocin (STZ) (50 mg/kg, i.p., single dose) to induce experimental diabetes mellitus. The development of diabetic AKI was assessed biochemically and histologically. In addition, the diabetes-induced lipid profile and renal oxidative stress were assessed. The single dose of STZ produced diabetes, which induced renal oxidative stress, altered the lipid profile and subsequently produced kidney injuryAKI in 7 weeks by increasing serum creatinine, blood urea nitrogen (BUN), proteinuria, and glomerular damage. Treatment with fenofibrate and gemfibrozil (30 mg/kg p.o, 7 weeks) normalized the altered lipid profile by decreasing serum cholesterol, triglycerides, and increasing serum high-density lipoprotein in diabetic rats. Lisinopril (1 mg/kg, p.o., 7 weeks, reference compound) prevents lipid alteration and development of diabetic AKI.Result: Fenofibrate and gemfibrozil, besides hyperglycemia, significantly prevented the development of diabetic AKI by reducing (serum and tissue) oxidative stress, hyperlipidemia, serum BUN, creatinine, and urinary protein. Further, fenofibrate, but not gemfibrozil, considerably reduced renal structural and functional abnormalities in diabetic rats. The fenofibrate was more effective in attenuating the diabetes-induced AKI and renal oxidative stress as compared to treatment with and gemfibrozil.Conclusion: The fenofibrate and gemfibrozil treatment markedly prevented the diabetes-induced AKI. In comparison, the fenofibrate is found to be a superior approach to attenuate the diabetic AKI than gemfibrozil.

Hematopietic Stem Cells with Defects in the NF-κB Alternative Pathway Show a Deficient Repopulation Capacity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1269-1269
Author(s):  
Lucia Fernandez ◽  
Africa Gonzalez ◽  
Carmen Sanchez-Valdepeñas ◽  
Luis Madero ◽  
Roland M Schmid ◽  
...  
Keyword(s):  
Stem Cells ◽  
Blood Cells ◽  
Conflicts Of Interest ◽  
Alternative Pathway ◽  
High Dose ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Deficient Mice ◽  
Marrow Cells

Abstract Abstract 1269 Hematopoietic stem cells (HSCs) maintain the production of all blood cells through the lifespan of an organism, and regenerate the whole hematopoietic system after stressful episodes such as high dose chemotherapy or upon transplantation. The functions of HSCs in these 2 situations, steady-state and under stress, are controlled by a variety of molecules, which may provide different contribution to each process. We investigated whether the NF-kB alternative pathway might have a role in HSCs functions, using mice deficient for two components of this pathway: NF-kB-inducing kinase (NIK) or p52. The activation of NIK is generally known as the alternative (or non-canonical) NF-kB pathway, and drives the post-translational processing of p100 to mature p52, which results in the translocation to the nucleus of p52-containing complexes such as p52/RelB. Apart from the already reported defects in B-cell maturation, both NIK- and p52-deficient mice did not present major disturbances in blood cells numbers. The absolute numbers of marrow cells were not different among the knocked-out and the wild-type mice. We first studied the compartment of marrow cells known to be enriched for HSCs, either lineage-depleted Sca1-positive ckit-positive cells (LSK), or CD150 positive CD48 negative cells. The proportions of marrow cells with the immunophenotype of HSCs in either NIK-deficient or p52-deficient mice were similar to those in control mice. The amount of clonogeneic progenitor cells in the marrow was assessed in standard CFU-GM cultures, and gave no differences in output in any of the mice studied. We set up in vitro liquid cultures with murine stem cell factor and human interleukin-11, and determined the cellular production weekly. Cultures started with NIK-deficient marrow cells produced significantly less numbers of cells and CFU-GM, compared with those started with wild type marrow. This deficit in hematopoietic capacity was further confirmed in a more stringent assay of HSC function, the in vivo competitive repopulation assay. Equal numbers of lineage-depleted (Lin-) CD45.2 marrow cells of either NIK-deficient, p52-deficient or wild-type mice, were mixed with Lin- CD45.1 marrow cells of syngeneic mice, and transplanted into lethally irradiated CD45.1 recipients. Four months after transplant, the chimeric status and the hematopoietic lineage repopulation of CD45.2 cells was assessed in peripheral blood (PB). NIK- or p52-deficient HSCs repopulated the B-, T- and myeloid-lineages but at significantly lower levels when compared to wild type HSCs. Total donor CD45.2 cells and total CD45.2 LSK cells were also significantly lower in the marrows of mice transplanted with NIK- or p52-deficient HSCs versus those of controls. We used the marrows of the repopulated mice for secondary transplants, and confirmed the defect in the repopulating capacity of NIK- and p52-deficient HSCs. Our results suggest that the NF-kB alternative pathway plays a role in the function of HSCs, and this role may be important under stress conditions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Tissue-specific induction of 17 beta-hydroxysteroid dehydrogenase type IV by peroxisome proliferator chemicals is dependent on the peroxisome proliferator-activated receptor alpha

1998 ◽  
Vol 158 (2) ◽  
pp. 237-246 ◽  
Author(s):  
LQ Fan ◽  
RC Cattley ◽  
JC Corton
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Ppar Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Protein Levels ◽  
Type Iv ◽  
Liver And Kidney ◽  
The Impact

The 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) family of proteins regulates the levels of the active 17 beta-hydroxy forms of sex steroids. The expression of 17 beta-HSD type IV is induced by peroxisome proliferator chemicals (PPC) in rat liver. In order to characterize more generally the impact of PPC on 17 beta-HSD expression, we determined (1) if expression of other members of the 17 beta-HSD family was coordinately induced by PPC exposure, (2) the tissues in which 17 beta-HSD was induced by PPC, and (3) whether the induction of 17 beta-HSD by PPC was dependent on the peroxisome proliferator-activated receptor alpha (PPAR alpha), the central mediator of PPC effects in the mouse liver. The mRNA levels of 17 beta-HSD I, II, and III were not altered in the liver, kidney, and testis or uterus of rats treated with PPC. The mRNA or 80 kDa a full-length protein levels of 17 beta-HSD IV were strongly induced in liver and kidney, but not induced in adrenals, brown fat, heart, testis, and uterus of rats treated with diverse PPC. In liver and kidneys from treated rats, additional proteins of 66 kDa, 56 kDa, and 32 kDa were also induced which reacted with the anti-17 beta-HSD IV antibodies and were most likely proteolytic fragments of 17 bega-HSD IV. Treatment of mice which lack a functional form of PPAR alpha with PPC, demonstrated that PPC-inducibility of 17 beta-HSD IV mRNA or the 80 kDa protein was dependent on PPAR alpha expression in liver and kidney. Our results demonstrate that 17 beta-HSD IV is induced by PPC through a PPAR alpha-dependent mechanism and support the hypothesis that exposure to PPC leads to alterations in sex steroid metabolism.

scholarly journals Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells

2016 ◽  
Vol 57 (2) ◽  
pp. 87-96 ◽  
Author(s):  
Kent Wehmeier ◽  
Luisa M Onstead-Haas ◽  
Norman C W Wong ◽  
Arshag D Mooradian ◽  
Michael J Haas
Keyword(s):  
Vitamin D ◽  
Signaling Pathways ◽  
Hepg2 Cells ◽  
Density Lipoprotein ◽  
Hepatic Function ◽  
Peroxisome Proliferator ◽  
Dihydroxyvitamin D3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Hydroxyvitamin D

The vitamin D metabolite 24,25-dihydroxyvitamin D3(24, 25[OH]2D3) was shown to induce nongenomic signaling pathways in resting zone chondrocytes and other cells involved in bone remodeling. Recently, our laboratory demonstrated that 24,25-[OH]2D3but not 25-hydroxyvitamin D3, suppresses apolipoprotein A-I (apo A-I) gene expression and high-density lipoprotein (HDL) secretion in hepatocytes. Since 24,25-[OH]2D3has low affinity for the vitamin D receptor (VDR) and little is known with regard to how 24,25-[OH]2D3modulates nongenomic signaling in hepatocytes, we investigated the capacity of 24,25-[OH]2D3to activate various signaling pathways relevant to apo A-I synthesis in HepG2 cells. Treatment with 24,25-[OH]2D3resulted in decreased peroxisome proliferator-activated receptor alpha (PPARα) expression and retinoid-X-receptor alpha (RXRα) expression. Similarly, treatment of hepatocytes with 50 nM 24,25-[OH]2D3for 1–3 h induced PKCα activation as well as c-jun-N-terminal kinase 1 (JNK1) activity and extracellular-regulated kinase 1/2 (ERK1/2) activity. These changes in kinase activity correlated with changes in c-junphosphorylation, an increase in AP-1-dependent transcriptional activity, as well as repression of apo A-I promoter activity. Furthermore, treatment with 24,25-[OH]2D3increased IL-1β, IL-6, and IL-8 expression by HepG2 cells. These observations suggest that 24,25-[OH]2D3elicits several novel rapid nongenomic-mediated pro-inflammatory protein kinases targeting AP1 activity, increasing pro-inflammatory cytokine expression, potentially impacting lipid metabolism and hepatic function.

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