P2591Circulating pro fibrotic protein promotes fibrosis in liver and heart

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Tsukano ◽  
I Shimizu ◽  
Y Yoshida ◽  
R Ikegami ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cardiac Fibrosis ◽  
Peptide Vaccine ◽  
Transcript Level ◽  
Mice Model ◽  
Nash Model ◽  
Age Related ◽  
Brown Adipose ◽  
Micro Array

Abstract Analyzing two sets of DNA micro array data with bioinformatics, we identified a secreted form pro-fibrotic protein (sPFP) expressed in dysfunctional brown adipose tissue (BAT) in mice. Testing our biobank samples, we found this protein increased in plasma of non-alcoholic steatohepatitis (NASH) patients or aged individuals. We generated a murine obese NASH model by imposing a high fat diet in C57BL/6NCr mice for 9–10 months since 4 weeks of age, and found that sPFP is produced predominantly by BAT. In this model, we also found that sPFP increased in plasma. We generated a murine systemic sPFP knockout (KO) model and found that liver fibrosis ameliorated in sPFP-KO model. We also suppressed circulating sPFP with a peptide vaccine targeting this molecule, and found that sPFP vaccination therapy inhibited liver fibrosis. Next, we generated sPFP gain of function (GOF) model by the administration of plasmid encoding sPFP into skeletal muscle. Liver fibrosis augmented in sPFP-GOF model, and these results suggested that sPFP has causal role for the progression of fibrotic response in liver. In the obese NASH model, we found that cardiac fibrosis also developed and it ameliorated in sPFP-KO model, indicating that sPFP may have pathological roles for heart failure with preserved ejection fraction (HFpEF) related with age-related disorders. In addition to an increase in circulating sPFP in aged individuals, we found that sPFP increased in BAT of chronological aged mice model. In vitro studies with differentiated brown adipocytes showed that c-Fos upregulated sPFP in transcript level. Our results suggest that sPFP contributes for the progression of fibrotic responses in obese or aged models. Inhibition of sPFP may become a therapy for NASH or HFpEF.

Circulating pro fibrotic protein promotes fibrosis in liver

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hsiao ◽  
I Shimizu ◽  
Y Yoshida ◽  
R Ikegami ◽  
Y Hayashi ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
High Fat Diet ◽  
In Vitro Studies ◽  
High Fat ◽  
Brown Adipocytes ◽  
Adipose Tissues ◽  
Nash Model ◽  
Brown Adipose

Abstract Background/Introduction Non-alcoholic steatohepatitis (NASH), driven by the obesity epidemic, has become the most common form of liver disease. Inflamed visceral adipose tissue secretes pro-inflammatory adipokines that are causal for systemic metabolic disorders. Role of adipokines in NASH, especially those from brown adipose tissues (BATokine) remain unclear. Purpose To show the pathogenic role of BATokine in NASH. Methods To identify and characterize the pathological roles of pro-fibrotic BATokine, we generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and murine systemic or BAT specific knockout (KO) models. We also conducted functional in-vitro studies with differentiated brown adipocytes. Results Analyzing two sets of DNA micro array data with bioinformatics, we identified a secreted form pro-fibrotic protein (sPFP) expressed in dysfunctional brown adipose tissues (BAT) in mice. Testing our biobank samples, we found this protein increased in plasma of NASH patients. We generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice for 9–10 months since 4 weeks of age, and found that sPFP is produced predominantly by BAT. In this model, we also found that sPFP increased in plasma. We generated a murine systemic or BAT specific sPFP knockout (KO) models and found that liver fibrosis ameliorated in these models. We also suppressed circulating sPFP with a peptide vaccine targeting this molecule, and found that sPFP vaccination therapy inhibited liver fibrosis. Next, we generated sPFP gain of function (GOF) model by the administration of plasmid encoding sPFP into skeletal muscle. Liver fibrosis augmented in sPFP-GOF model, and these results suggested that sPFP has causal role for the progression of fibrotic response in liver. In vitro studies with differentiated brown adipocytes showed that metabolic stress increased c-Fos in nuclear, and this was causal for an increase in sPFP level. Conclusions Our results suggest that one of the BATokines, sPFP, contributes for the progression of fibrotic responses in obese-NASH model. Inhibition of sPFP may become a therapy for NASH or obesity related fibrotic disorders. Funding Acknowledgement Type of funding source: None

scholarly journals Curcumin improves age-related and surgically induced osteoarthritis by promoting autophagy in mice

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Guowang Zhang ◽  
Jiaqing Cao ◽  
Erzhu Yang ◽  
Bo Liang ◽  
Jianing Ding ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
B Cell Lymphoma ◽  
In Vivo Studies ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Mice Model ◽  
Curcumin Treatment ◽  
Chondrocyte Death ◽  
Age Related ◽  
Surgically Induced

Reduced autophagy has been implied in chondrocyte death and osteoarthritis. Curcumin (Cur) owns therapeutic effect against osteoarthritis (OA) and enhances autophagy in various tumor cells. Whether the cartilage protection of curcumin is associated with autophagy promotion and the potential signaling pathway involved remains unclear. The present study aimed to investigate the role of autophagy in the anti-OA activity of curcumin using spontaneous and surgically induced OA mice model. Spontaneous and surgically induced OA mice model was established and treated with Cur. Articular cartilage destruction and proteoglycan loss were scored through Safranin O/Fast green staining. Apoptotic cell death was detected with TUNEL (terminal deoxynucleotidyl transferase-mediated dTUP-biotin nick end labeling assay) staining and Western blot for caspase-3, Bcl-2 associated X protein (Bax), and Bcl-2 (B-cell lymphoma-2). Light chain 3 (LC3) immunohistochemistry was used to evaluate autophagy. In vitro, primary chondrocytes were treated with interleukin 1 beta (IL-1β) and Cur. Autophagy was inhibited using 3-methyladenine. Apoptosis and autophagy were detected using flow cytometry and Western blotting assay. Curcumin treatment enhanced autophagy, reduced apoptosis, and cartilage loss in both OA models. In vitro, curcumin treatment improved IL-1β induced autophagy inhibition, cell viability decrease, and apoptosis. Mechanistically, in vivo studies suggested curcumin promoted autophagy through regulating Akt/mTOR pathway. In conclusion, our results demonstrate that curcumin-induced autophagy via Akt/mTOR signaling pathway contributes to the anti-OA effect of curcumin.

Effects of age, gender, and senescence on β-adrenergic responses of isolated F344 rat brown adipocytes in vitro

1998 ◽  
Vol 274 (4) ◽  
pp. E726-E736 ◽  
Author(s):  
Annette M. Gabaldón ◽  
Roger B. McDonald ◽  
Barbara A. Horwitz
Keyword(s):  
Uncoupling Protein ◽  
Physiological State ◽  
Gender Effects ◽  
Rapid Weight Loss ◽  
Brown Adipocytes ◽  
Cl 316,243 ◽  
Age Related ◽  
Brown Adipose ◽  
Camp Levels

We previously reported greater age-related attenuation of cold-induced thermoregulation and brown adipose tissue thermogenic capacity in male vs. female F344 rats. With onset of the rapid weight loss that occurs near the end of the lifespan, this age-related attenuation becomes severe. We refer to this “end-of-life” physiological state of older rats as senescence. Here, we measured oxygen consumption of isolated brown adipocytes and found no age (6 vs. 12 vs. 26 mo) or gender effects on maximal norepinephrine (NE)- or CL-316,243 (β3-adrenergic agonist)-induced responses. In contrast, brown adipocytes from 22- to 26-mo-old senescent rats (males and females) consumed 51–60% less oxygen during maximal stimulation with NE and CL-316,243 than did cells from 26-mo-old presenescent rats. This attenuation was associated with lower (65–72%) uncoupling protein 1 concentrations but no alterations in NE-induced cAMP levels or lipolysis. Our data indicate that senescence, but not chronological age, significantly impacts NE-/β3-mediated thermogenesis of isolated brown adipocytes and that this effect involves altered mitochondrial rather than altered membrane or cytosol events.

scholarly journals Identification of RIFL, a novel adipocyte-enriched insulin target gene with a role in lipid metabolism

2012 ◽  
Vol 303 (3) ◽  
pp. E334-E351 ◽  
Author(s):  
Gang Ren ◽  
Ji Young Kim ◽  
Cynthia M. Smas
Keyword(s):  
Lipid Metabolism ◽  
Transcriptional Profiling ◽  
Serum Triglyceride ◽  
Transcript Level ◽  
Wild Type ◽  
New Genes ◽  
Brown Adipose ◽  
Genes Encoding ◽  
Triglyceride Content

To identify new genes that are important in fat metabolism, we utilized the Lexicon-Genentech knockout database of genes encoding transmembrane and secreted factors and whole murine genome transcriptional profiling data that we generated for 3T3-L1 in vitro adipogenesis. Cross-referencing null models evidencing metabolic phenotypes with genes induced in adipogenesis led to identification of a new gene, which we named RIFL (refeeding induced fat and liver). RIFL-null mice have serum triglyceride levels approximately one-third of wild type. RIFL transcript is induced >100-fold during 3T3-L1 adipogenesis and is also increased markedly during adipogenesis of murine and human primary preadipocytes. siRNA-mediated knockdown of RIFL during 3T3-L1 adipogenesis results in an ∼35% decrease in adipocyte triglyceride content. Murine RIFL transcript is highly enriched in white and brown adipose tissue and liver. Fractionation of WAT reveals that RIFL transcript is exclusive to adipocytes with a lack of expression in stromal-vascular cells. Nutritional and hormonal studies are consistent with a prolipogenic function for RIFL. There is evidence of an approximately eightfold increase in RIFL transcript level in WAT in ob/ob mice compared with wild-type mice. RIFL transcript level in WAT and liver is increased ∼80- and 12-fold, respectively, following refeeding of fasted mice. Treatment of 3T3-L1 adipocytes with insulin increases RIFL transcript ≤35-fold, whereas agents that stimulate lipolysis downregulate RIFL. Interestingly, the 198-amino acid RIFL protein is predicted to be secreted and shows ∼30% overall conservation with the NH2-terminal half of angiopoietin-like 3, a liver-secreted protein that impacts lipid metabolism. In summary, our data suggest that RIFL is an important new regulator of lipid metabolism.

Assessment of fat-specific protein 27 in the adipocyte lineage suggests a dual role for FSP27 in adipocyte metabolism and cell death

2008 ◽  
Vol 294 (4) ◽  
pp. E654-E667 ◽  
Author(s):  
Ji Young Kim ◽  
Kun Liu ◽  
Shengli Zhou ◽  
Kristin Tillison ◽  
Yu Wu ◽  
...  
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Ectopic Expression ◽  
Transcript Level ◽  
Specific Protein ◽  
Fatty Acid Binding ◽  
Brown Adipose ◽  
Tnf Α ◽  
Human Preadipocytes

Fat-specific protein 27 (FSP27)/CIDEC was initially identified by its upregulation in TA1 adipogenesis and is one of three cell death-inducing DFF45-like effector (CIDE) family proapoptotic proteins. Ectopic expression of CIDEs promotes apoptosis of mammalian cells. On the other hand, FSP27 has very recently been illustrated to regulate lipid droplet size and promote lipid storage in adipocytes. Regulation of endogenous FSP27 expression is unknown. We assessed the FSP27 transcript level in the well-characterized 3T3-L1 in vitro adipocyte differentiation model and found its emergence parallels the adipocyte-enriched transcript adipocyte fatty acid binding protein and stearoyl Co-A desaturase 1. Furthermore, FSP27 is a differentiation-dependent transcript in adipogenesis of primary rodent and human preadipocytes and in brown adipogenesis. The FSP27 transcript is inversely regulated by TNF-α and insulin, consistent with an antilipolytic function. It is nearly abolished with a 4-h exposure of 3T3-L1 adipocytes to 10 ng/ml TNF-α, while treatment with 100 nM insulin increased the FSP27 transcript eightfold. In the latter case LY-294002 blocked this response, indicating involvement of phosphatidylinositol 3-kinase signals. Northern blot analysis of murine tissues indicated exclusive expression of FSP27 in white and brown adipose tissue; however, a dramatic upregulation occurred in the liver of ob/ob mice. Ectopic expression of murine FSP27 in 293T cells and in 3T3-L1 preadipocytes led to the appearance of key apoptotic hallmarks and cell death. However, despite the upregulation for FSP27 in adipogenesis, we failed to detect DNA laddering indicative of apoptosis in 3T3-L1 adipocytes. This suggests that adipogenesis is accompanied by decreased susceptibility to the proapoptotic effects of FSP27. Overall, our findings support roles for FSP27 in cell death and in adipocyte function.

scholarly journals Orexin Restores Aging-Related Brown Adipose Tissue Dysfunction in Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 485-501 ◽  
Author(s):  
Dyan Sellayah ◽  
Devanjan Sikder
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Fat Mass ◽  
Core Body Temperature ◽  
Brown Adipocyte ◽  
Aged Mice ◽  
Age Related ◽  
Brown Adipose ◽  
The Impact

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with interscapular BAT morphologic abnormalities and thermogenic dysfunction. In vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphologic characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy. Our results suggest a role for orexin (OX) signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass were accelerated in mice in which OX-producing neurons were ablated. Conversely, OX injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.

Abstract 331: Mir-433 Controls Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Lichan Tao ◽  
Xiaoting Wu ◽  
Ping Chen ◽  
Shanshan Li ◽  
Xiaomin Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Mice Model ◽  
Ki 67 ◽  
End Stage ◽  
Common Manifestation

Background: Cardiac fibrosis, a result of multiple injurious insults in heart, is a final common manifestation of chronic heart diseases and can lead to end-stage cardiac failure. MicroRNAs (miRNAs, miRs) participate in many essential biological processes and their dysfunction has been implicated in a variety of cardiovascular diseases including fibrosis. miR-433 has recently been implicated in renal fibrosis, however, its role in cardiac fibrosis is unclear. Methods and results: miR-433 was increased in heart samples from dilated cardiomyopathy patients as determined by qRT-PCRs. In addition, miR-433 was also consistently upregulated in mice model of cardiac fibrosis after myocardial infarction or heart failure. Additionally, miR-433 was found to be enriched in fibroblasts compared to cardiomyocytes. In neonatal cardiac fibroblasts, forced expression of miR-433 promoted cell proliferation as indicated by EdU and Ki-67 staining. Moreover, miR-433 overexpression promoted the transdifferentiation of fibroblasts into myofibroblasts as determined by qRT-PCR and western blot for α-SMA and collagen whether in the presence of TGF-β or not, indicating that miR-433 is sufficient to induce fibrosis. In addition, knockdown of miR-433 inhibited proliferation and the transdifferentiation into myofibroblasts, indicating that miR-433 is required for cardiac fibrosis. Interestingly, miR-433 did not affect the migration of cardiac fibroblast. Importantly, miR-433 antagomir could partially attenuate cardiac fibrosis induced by myocardial infarction in mice. Conclusion: both in vitro and in vivo. Inhibition of miR-433 represents a novel therapeutic strategy for cardiac fibrosis.

Obesity associated pro-fibrotic protein augments fibrosis in heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Tsukano ◽  
I Shimizu ◽  
Y Yoshida ◽  
Y Hsiao ◽  
R Ikegami ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Sterile Inflammation ◽  
Stressed Condition ◽  
Mice Model ◽  
Dna Microarray Data ◽  
Brown Adipose ◽  
Dietary Obesity ◽  
Fibrotic Disorders

Abstract   Chronic sterile inflammation in visceral fat has causal roles for systemic metabolic disorders in obesity. Inflamed visceral adipose tissue secretes pro-inflammatory adipokines, and this contributes to tissue remodeling under a metabolically stressed condition. Various kinds of white adipokines are broadly studied, however, roles of brown adipose tissue (BAT) derived adipokines (BATokine) remain to be explored. In this project, we tried to characterize pathogenic role of BATokine in obesity related fibrotic disorders, especially focusing on heart failure with preserved ejection fraction (HFpEF). For this purpose, we analyzed two sets of DNA microarray data, and identified an obesity associated pro-fibrotic protein (OAFP) as a possible pathogenic BATokine. Our biobank studies showed OAFP increased in patients with diastolic dysfunction, and E/e' analyzed with cardiac echo increased in direct proportion to circulating OAFP level in humans. We generated dietary obese mice model, and found OAFP increased both in BAT and circulation. We generated a murine systemic or BAT specific OAFP knockout (KO) models, and found that obesity-induced diastolic dysfunction ameliorated in these models. Cardiac fibrosis was also suppressed by genetic depletion of OAFP. We found OAFP increased in circulation in aged humans and mice, and studies in chronologically aged mice showed this molecule increased in BAT with aging. Our results indicate that OAFP is secreted predominantly from BAT, and mediates pathogenic roles by augmenting cardiac fibrosis in dietary obesity or aging. Suppression of OAFP may become a therapy for HFpEF. Funding Acknowledgement Type of funding source: None

scholarly journals Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

2017 ◽  
Vol 41 (3) ◽  
pp. 849-864 ◽  
Author(s):  
Yanqing Zhang ◽  
Pingping Liao ◽  
Meng’en Zhu ◽  
Wei Li ◽  
Dan Hu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Dysfunction ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Pressure Overload ◽  
Protective Effects ◽  
Mice Model ◽  
Ischaemic Injury

Background/Aims: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. Methods: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. Results: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARβ/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARβ/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. Conclusions: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

scholarly journals Silencing of lncRNA AK045490 Promotes Osteoblast Differentiation and Bone Formation via β-Catenin/TCF1/Runx2 Signaling Axis

2019 ◽  
Vol 20 (24) ◽  
pp. 6229 ◽  
Author(s):  
Dijie Li ◽  
Ye Tian ◽  
Chong Yin ◽  
Ying Huai ◽  
Yipu Zhao ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Noncoding Rna ◽  
Osteoblast Differentiation ◽  
Nuclear Translocation ◽  
Mice Model ◽  
Structural Deterioration ◽  
Age Related

Osteoporosis, a disease characterized by both loss of bone mass and structural deterioration of bone, is the most common reason for a broken bone among the elderly. It is known that the attenuated differentiation ability of osteogenic cells has been regarded as one of the greatest contributors to age-related bone formation reduction. However, the effects of current therapies are still unsatisfactory. In this study we identify a novel long noncoding RNA AK045490 which is correlated with osteogenic differentiation and enriched in skeletal tissues of mice. In vitro analysis of bone-derived mesenchymal stem cells (BMSCs) showed that AK045490 inhibited osteoblast differentiation. In vivo inhibition of AK045490 by its small interfering RNA rescued bone formation in ovariectomized osteoporosis mice model. Mechanistically, AK045490 inhibited the nuclear translocation of β-catenin and downregulated the expression of TCF1, LEF1, and Runx2. The results suggest that Lnc-AK045490 suppresses β-catenin/TCF1/Runx2 signaling and inhibits osteoblast differentiation and bone formation, providing a novel mechanism of osteogenic differentiation and a potential drug target for osteoporosis.

Sign in / Sign up

Export Citation Format

Share Document