scholarly journals Hepatocyte-specific PPARA expression exclusively promotes agonist-induced cell proliferation without influence from nonparenchymal cells

2017 ◽  
Vol 312 (3) ◽  
pp. G283-G299 ◽  
Author(s):  
Chad N. Brocker ◽  
Jiang Yue ◽  
Donghwan Kim ◽  
Aijuan Qu ◽  
Jessica A. Bonzo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Lipid Metabolism ◽  
Target Genes ◽  
Elevated Serum ◽  
Hepatocyte Proliferation ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Nonparenchymal Cells ◽  
Specific Regulation

Peroxisome proliferator-activated receptor-α (PPARA) is a nuclear transcription factor and key mediator of systemic lipid metabolism. Prolonged activation in rodents causes hepatocyte proliferation and hepatocellular carcinoma. Little is known about the contribution of nonparenchymal cells (NPCs) to PPARA-mediated cell proliferation. NPC contribution to PPARA agonist-induced hepatomegaly was assessed in hepatocyte ( Ppara△Hep)- and macrophage ( Ppara△Mac)-specific Ppara null mice. Mice were treated with the agonist Wy-14643 for 14 days, and response of conditional null mice was compared with conventional knockout mice ( Ppara−/−). Wy-14643 treatment caused weight loss and severe hepatomegaly in wild-type and Ppara△Mac mice, and histological analysis revealed characteristic hepatocyte swelling; Ppara△Hep and Ppara−/− mice were protected from these effects. Ppara△Mac serum chemistries, as well as aspartate aminotransferase and alanine aminotransferase levels, matched wild-type mice. Agonist-treated Ppara△Hep mice had elevated serum cholesterol, phospholipids, and triglycerides when compared with Ppara−/− mice, indicating a possible role for extrahepatic PPARA in regulating circulating lipid levels. BrdU labeling confirmed increased cell proliferation only in wild-type and Ppara△Mac mice. Macrophage PPARA disruption did not impact agonist-induced upregulation of lipid metabolism, cell proliferation, or DNA damage and repair-related gene expression, whereas gene expression was repressed in Ppara△Hep mice. Interestingly, downregulation of inflammatory cytokines IL-15 and IL-18 was dependent on macrophage PPARA. Cell type-specific regulation of target genes was confirmed in primary hepatocytes and Kupffer cells. These studies conclusively show that cell proliferation is mediated exclusively by PPARA activation in hepatocytes and that Kupffer cell PPARA has an important role in mediating the anti-inflammatory effects of PPARA agonists.

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-α agonist ciprofibrate

2003 ◽  
Vol 15 (1) ◽  
pp. 9-19 ◽  
Author(s):  
Fekadu Yadetie ◽  
Astrid Laegreid ◽  
Ingunn Bakke ◽  
Waclaw Kusnierczyk ◽  
Jan Komorowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Candidate Genes ◽  
Stress Responses ◽  
Inflammatory Responses ◽  
Sugar Metabolism ◽  
Hepatocyte Proliferation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver Gene

Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-α (PPARα), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPARα agonist-responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate-dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate-dosed rats, and some of these are potential targets of PPARα. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.

Dietary isoflavone supplementation modulates lipid metabolism via PPARα-dependent and -independent mechanisms

2006 ◽  
Vol 26 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Orsolya Mezei ◽  
Yilan Li ◽  
Eimear Mullen ◽  
Jennifer S. Ross-Viola ◽  
Neil F. Shay
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Soy Protein ◽  
Knockout Mice ◽  
Estrogenic Activity ◽  
Serum Triglyceride ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Serum Triglycerides ◽  
Regulated Gene Expression

Intake of soy protein has been associated with improvements in lipid metabolism, with much attention being focused on the serum cholesterol-lowering property of soy. The component or components of soy that are responsible for improvements in lipid metabolism have been investigated and their specific actions debated. One component, the isoflavones, has been shown to have weak estrogenic activity, and recently, several research groups have suggested that isoflavones are activating peroxisome proliferator-activated receptors (PPARs). The three different isoforms of PPARs (α, γ, and δ) have overlapping tissue distributions and functions associated with lipid metabolism. The goal of the present study was to investigate the hypothesis that the effect of isoflavones is mediated through the PPARα receptor. Male and female 129/Sv mice were obtained, including both wild-type and genetically altered PPARα knockout mice. Groups of mice were fed high-fat atherogenic diets containing soy protein +/- isoflavones and PPARα agonist fenofibrate for 6 wk. At the end of 6 wk, serum and tissue lipid levels were measured along with hepatic gene expression. Most notably, serum triglycerides were reduced by isoflavone consumption. Compared with intake of a low-isoflavone basal diet, isoflavone intake reduced serum triglyceride levels by 36 and 52% in female and male wild-type mice, respectively, compared with 55 and 52% in fenofibrate-treated mice. Isoflavones also improved serum triglyceride levels in knockout mice, whereas fenofibrate did not, suggesting that two different regulatory mechanisms may be affected by isoflavone intake. Isoflavone intake resembled action of fenofibrate on PPARα-regulated gene expression, although less robustly compared with fenofibrate. We suggest that, at the levels consumed in this study, isoflavone intake is altering lipid metabolism in a manner consistent with activation of PPARα and also via a PPARα-independent mechanism as well.

scholarly journals Hepatic sirtuin 1 is dispensable for fibrate-induced peroxisome proliferator-activated receptor-α function in vivo

2014 ◽  
Vol 306 (7) ◽  
pp. E824-E837 ◽  
Author(s):  
Jessica A. Bonzo ◽  
Chad Brocker ◽  
Changtao Jiang ◽  
Rui-Hong Wang ◽  
Chu-Xia Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Target Genes ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor-α (PPARα) mediates metabolic remodeling, resulting in enhanced mitochondrial and peroxisomal β-oxidation of fatty acids. In addition to the physiological stimuli of fasting and high-fat diet, PPARα is activated by the fibrate class of drugs for the treatment of dyslipidemia. Sirtuin 1 (SIRT1), an important regulator of energy homeostasis, was downregulated in fibrate-treated wild-type mice, suggesting PPARα regulation of Sirt1 gene expression. The impact of SIRT1 loss on PPARα functionality in vivo was assessed in hepatocyte-specific knockout mice that lack the deacetylase domain of SIRT1 ( Sirt1 ΔLiv). Knockout mice were treated with fibrates or fasted for 24 h to activate PPARα. Basal expression of the PPARα target genes Cyp4a10 and Cyp4a14 was reduced in Sirt1 ΔLiv mice compared with wild-type mice. However, no difference was observed between wild-type and Sirt1 ΔLiv mice in either fasting- or fibrate-mediated induction of PPARα target genes. Similar to the initial results, there was no difference in fibrate-activated PPARα gene induction. To assess the relationship between SIRT1 and PPARα in a pathophysiological setting, Sirt1 ΔLiv mice were maintained on a high-fat diet for 14 wk, followed by fibrate treatment. Sirt1 ΔLiv mice exhibited increased body mass compared with control mice. In the context of a high-fat diet, Sirt1 ΔLiv mice did not respond to the cholesterol-lowering effects of the fibrate treatment. However, there were no significant differences in PPARα target gene expression. These results suggest that, in vivo, SIRT1 deacetylase activity does not significantly impact induced PPARα activity.

scholarly journals Rel Induces Interferon Regulatory Factor 4 (IRF-4) Expression in Lymphocytes

2000 ◽  
Vol 191 (8) ◽  
pp. 1281-1292 ◽  
Author(s):  
Raelene J. Grumont ◽  
Steve Gerondakis
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Nuclear Factor Κb ◽  
Wild Type ◽  
Cell Type ◽  
Regulatory Factor ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Interferon Regulatory Factor 4

In lymphocytes, the Rel transcription factor is essential in establishing a pattern of gene expression that promotes cell proliferation, survival, and differentiation. Here we show that mitogen-induced expression of interferon (IFN) regulatory factor 4 (IRF-4), a lymphoid-specific member of the IFN family of transcription factors, is Rel dependent. Consistent with IRF-4 functioning as a repressor of IFN-induced gene expression, the absence of IRF-4 expression in c-rel−/− B cells coincided with a greater sensitivity of these cells to the antiproliferative activity of IFNs. In turn, enforced expression of an IRF-4 transgene restored IFN modulated c-rel−/− B cell proliferation to that of wild-type cells. This cross-regulation between two different signaling pathways represents a novel mechanism that Rel/nuclear factor κB can repress the transcription of IFN-regulated genes in a cell type–specific manner.

scholarly journals Differences in Gene Expression between Wild Type and Hoxa1 Knockout Embryonic Stem Cells after Retinoic Acid Treatment or Leukemia Inhibitory Factor (LIF) Removal

2005 ◽  
Vol 280 (16) ◽  
pp. 16484-16498 ◽  
Author(s):  
Eduardo Martinez-Ceballos ◽  
Pierre Chambon ◽  
Lorraine J. Gudas
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Retinoic Acid ◽  
Leukemia Inhibitory Factor ◽  
Target Genes ◽  
Hox Genes ◽  
Es Cells ◽  
Embryonic Stem ◽  
Inhibitory Factor ◽  
Hoxa Cluster

Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of theHoxa1gene, the most 3′ member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1-/-embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1-/-mutant blastocysts to study the Hoxa1 signaling pathway. We have characterized in detail these Hoxa1-/-ES cells by performing microarray analyses, and by this technique we have identified a number of putative Hoxa-1 target genes, including genes involved in bone development (e.g. Col1a1,Postn/Osf2, and the bone sialoprotein gene orBSP), genes that are expressed in the developing brain (e.g. Nnat,Wnt3a,BDNF,RhoB, andGbx2), and genes involved in various cellular processes (e.g. M-RAS,Sox17,Cdkn2b,LamA1,Col4a1,Foxa2,Foxq1,Klf5, andIgf2). Cell proliferation assays and Northern blot analyses of a number of ES cell markers (e.g. Rex1,Oct3/4,Fgf4, andBmp4) suggest that the Hoxa1 protein plays a role in the inhibition of cell proliferation by RA in ES cells. Additionally, Hoxa1-/-ES cells express high levels of various endodermal markers, includingGata4andDab2, and express much lessFgf5after leukemia inhibitory factor (LIF) withdrawal. Finally, we propose a model in which the Hoxa1 protein mediates repression of endodermal differentiation while promoting expression of ectodermal and mesodermal characteristics.

scholarly journals HOXA11 Regulates Chemoresistance By Modulating p53 Gene Expression in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5182-5182
Author(s):  
Xutao Guo ◽  
Bowen Yan ◽  
Yi Qiu
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
P53 Gene ◽  
Resistant Cell ◽  
Wild Type ◽  
P53 Expression ◽  
Acute Myeloid ◽  
Resistant Cells

Acute myeloid leukemia (AML) exhibits large intrinsic variation in drug responsiveness due to its inherent heterogeneity. Therefore, it is important to understand the resistant mechanism in order to improve the treatment. In our previously study, the OCI-AML2-resistant cell lines were established to resist cytarabine (Ara-C) in the concentration of 50 µM (OCI-AML2 R50). The RNA-seq results showed that many genes changed in the resistant cells compared to wild type OCI-AML2 cells. One of the most remarkably decreased gene in resistant cells was HOXA11 (Homeobox A11). It is the part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which regulates gene expression, morphogenesis, and differentiation. In this study, we have evaluated the importance of HOXA11 in AML chemoresistance. We found that knockdown of HOXA11 repressed the WT OCI-AML2 cell proliferation and increased the population of cells expressing CD123 and CD47 LSC (Leukemia stem cell) markers and enhanced the resistance to Ara-C in vitro, while overexpression of HOXA11 showed the reverse effect. These results support the idea that HOXA11 promotes drug sensitivity and apoptosis in AML. However, the result also showed that overexpression of HOXA11 repressed the OCI-AML2 R50 cell proliferation and enhanced the resistance. Therefore, HOXA11 plays opposite role in sensitive cells and resistant cells. We further investigated the mechanism for these effects. We found that knockdown of HOXA11 decreased the p53 gene expression and overexpression of HOXA11 increased the expression of p53 in OCI-AML2 and R50 cells. Further, in OCI-AML2 R50 cells p53 has a hotspot mutation in DNA binding site and studies have shown that p53 mutation enhance cancer cell survival and chemoresistance. Therefore, our study shows dual roles for HOXA11 in cell survival. In p53 wild type parental AML2 cells, HOXA11 induces wild type p53 expression to enhance drug sensitivity while in resistant cell, HOXA11 promotes mutant p53 expression and enhances the resistance of chemotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Lipid Metabolism Gene Expression And Cellularity of Intramuscular Adipocytes Within The Longissimus Muscle of Angus- And Wagyu-Sired Cattle When Raised To A Similar Age or Body Weight

2021 ◽  
Author(s):  
Jerad Jaborek ◽  
Francis Fluharty ◽  
Kichoon Lee ◽  
Henry Zerby ◽  
Alejandro Relling
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Binding Protein ◽  
Peroxisome Proliferator ◽  
Longissimus Muscle ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lipid Metabolism Gene ◽  
Metabolism Gene

Abstract Background: This study investigates intramuscular (IM) adipocyte development and growth in the Longissimus muscle (LM) between Wagyu- and Angus-sired steers compared at a similar age and days on feed (DOF) endpoint or similar body weight (BW) endpoint by measuring IM adipocyte cell area and lipid metabolism gene expression. Methods: Angus-sired steers (AN, n=6) were compared with steers from two different Wagyu sires, selected for either growth or marbling, to be compared at a similar DOF (WA-GD, n=5 and WA-MD, n=5) in experiment 1 or BW (WA-GB, n=4 and WA-MB, n=5) in experiment 2, respectively. Results: In experiment 1, WA-MD steers had a greater percentage of IM fat in the LM compared with AN and WA-GD steers. In experiment 2, WA-MB steers had a greater percentage of IM fat in the LM compared with AN and WA-GB steers. The distribution of IM adipocyte area was unimodal at all biopsy collections, with IM adipocyte area becoming progressively larger as cattle age and BW increased (P≤0.01). Peroxisome proliferator activated receptor delta (PPARd) was upregulated earlier for WA-MD and WA-MB cattle compared with other steers at a similar age and BW (P≤0.02; treatment×biopsy interaction). An earlier upregulation of PPARd is believed to have then upregulated peroxisome proliferator activated receptor gamma (PPARg) at a lesser BW for WA-MB steers (P=0.09; treatment×biopsy interaction), while WA-MD steers had a greater (P≤0.04) overall mean PPARg expression compared with other steers. Glycerol-3-phosphate acyltransferase, lipin 1, and hormone sensitive lipase demonstrated expression patterns similar to PPARg and PPARd or CCAAT enhancer binding protein beta, which emphasizes their importance in marbling development and growth. Additionally, WA-MD and WA-MB steers often had a greater early expression of fatty acid transporters (fatty acid transport protein 1; P<0.02; treatment×biopsy interaction) and binding proteins (fatty acid binding protein 4) compared with other steers. With many lipolytic genes upregulated at harvest, acetyl-CoA carboxylase beta may be inhibiting fatty acid oxidation in the LM to allow greater IM fat accumulation.Conclusions: Cattle with a greater marbling propensity appear to upregulate adipogenesis at a lesser maturity through PPARd, PPARg, and possibly adipogenic regulating compounds in lysophosphatidic acid and diacylglycerol.

Role of the Hypoxia-Inducible Factor Pathway in Normal and Osteoarthritic Meniscus and in Mice after Destabilization of the Medial Meniscus

Cartilage ◽  
2020 ◽  
pp. 194760352095814
Author(s):  
Austin V. Stone ◽  
Richard F. Loeser ◽  
Michael F. Callahan ◽  
Margaret A. McNulty ◽  
David L. Long ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Medial Meniscus ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Early Time ◽  
Wild Type ◽  
Inflammatory Stimuli ◽  
Hif Pathway

Objective Meniscus injury and the hypoxia-inducible factor (HIF) pathway are independently linked to osteoarthritis pathogenesis, but the role of the meniscus HIF pathway remains unclear. We sought to identify and evaluate HIF pathway response in normal and osteoarthritic meniscus and to examine the effects of Epas1 (HIF-2α) insufficiency in mice on early osteoarthritis development. Methods Normal and osteoarthritic human meniscus specimens were obtained and used for immunohistochemical evaluation and cell culture studies for the HIF pathway. Meniscus cells were treated with pro-inflammatory stimuli, including interleukins (IL)-1β, IL-6, transforming growth factor (TGF)-α, and fibronectin fragments (FnF). Target genes were also evaluated with HIF-1α and HIF-2α (Epas1) overexpression and knockdown. Wild-type ( n = 36) and Epas1+/− ( n = 30) heterozygous mice underwent destabilization of the medial meniscus (DMM) surgery and were evaluated at 2 and 4 weeks postoperatively for osteoarthritis development using histology. Results HIF-1α and HIF-2α immunostaining and gene expression did not differ between normal and osteoarthritic meniscus. While pro-inflammatory stimulation significantly increased both catabolic and anabolic gene expression in the meniscus, HIF-1α and Epas1 expression levels were not significantly altered. Epas1 overexpression significantly increased Col2a1 expression. Both wild-type and Epas1+/− mice developed osteoarthritis following DMM surgery. There were no significant differences between genotypes at either time point. Conclusion The HIF pathway is likely not responsible for osteoarthritic changes in the human meniscus. Additionally, Epas1 insufficiency does not protect against osteoarthritis development in the mouse at early time points after DMM surgery. The HIF pathway may be more important for protection against catabolic stress.

scholarly journals PGC-1α alternative promoter (Exon 1b) controls augmentation of total PGC-1α gene expression in response to cold water immersion and low glycogen availability

2020 ◽  
Vol 120 (11) ◽  
pp. 2487-2493
Author(s):  
R. Allan ◽  
J. P. Morton ◽  
G. L. Close ◽  
B. Drust ◽  
W. Gregson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cold Water ◽  
Water Immersion ◽  
Cold Water Immersion ◽  
Alternative Promoter ◽  
Future Research ◽  
Peroxisome Proliferator ◽  
Local Cooling ◽  
Post Exercise ◽  
Specific Regulation

AbstractThis investigation sought to determine whether post-exercise cold water immersion and low glycogen availability, separately and in combination, would preferentially activate either the Exon 1a or Exon 1b Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter. Through a reanalysis of sample design, we identified that the systemic cold-induced augmentation of total PGC-1α gene expression observed previously (Allan et al. in J Appl Physiol 123(2):451–459, 2017) was largely a result of increased expression from the alternative promoter (Exon 1b), rather than canonical promoter (Exon 1a). Low glycogen availability in combination with local cooling of the muscle (Allan et al. in Physiol Rep 7(11):e14082, 2019) demonstrated that PGC-1α alternative promoter (Exon 1b) expression continued to rise at 3 h post-exercise in all conditions; whilst, expression from the canonical promoter (Exon 1a) decreased between the same time points (post-exercise–3 h post-exercise). Importantly, this increase in PGC-1α Exon 1b expression was reduced compared to the response of low glycogen or cold water immersion alone, suggesting that the combination of prior low glycogen and CWI post-exercise impaired the response in gene expression versus these conditions individually. Data herein emphasise the influence of post-exercise cooling and low glycogen availability on Exon-specific control of total PGC-1 α gene expression and highlight the need for future research to assess Exon-specific regulation of PGC-1α.

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