The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model

Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR α/δ agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR α/δ agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model was used to test the pharmacodynamics and transcriptome regulation of GFT505 in this study. The results showed that GFT505 ameliorated hepatic steatosis, inflammation and fibrosis in CDAHFD mice model. RNA-sequencing yielded 3995 up-regulated and 3576 down-regulated genes with GFT505 treatment. And the most significant differentialy expressed genes involved in glucolipid metabolism (Pparα, Acox1, Cpt1b, Fabp4, Ehhadh, Fabp3), inflammation (Ccl6, Ccl9, Cxcl14) and fibrosis (Timp1, Lamc3, Timp2, Col3a1, Col1a2, Col1a1, Hapln4, Timp3, Pik3r5, Pdgfα, Pdgfβ, Tgfβ1, Tgfβ2) were confirmed by RT-qPCR. The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR α/δ agonist on NASH.

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Effect of Gender to Fat Deposition in Yaks Based on Transcriptomic and Metabolomics Analysis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.653188 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lin Xiong ◽

Jie Pei ◽

Xiaoyun Wu ◽

Qudratullah Kalwar ◽

Ping Yan ◽

...

Keyword(s):

Meat Quality ◽

Subcutaneous Fat ◽

Focal Adhesions ◽

Tca Cycle ◽

Fat Deposition ◽

Receptor Interaction ◽

Peroxisome Proliferator ◽

Steroid Synthesis ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Signaling

Fat deposition in yaks plays an important part in survival, multiplication, and meat quality. In this work, the characteristic of fat deposition in male yaks (MYs) and female yaks (FYs) and the regulations of gender to yak fat deposition were explored by mRNA-Seq and non-targeted metabolomics analyses. FYs possessed a higher body fat rate (BFR) of visceral fat, fat content in longissimus dorsi (LD) and liver, and subcutaneous fat thickness (p < 0.05). The fat and cholesterol synthesis in liver and the fat transport in FY blood increased. The fat metabolism in yaks is the combined effect of carbohydrate, fatty acid, and amino acid metabolism by tricarboxylic acid (TCA) cycle, and an increase of triglyceride (TG) synthesis was accompanied by an increase of steroid synthesis. The high levels of myo-inositol and cortisol (COR) (p < 0.01) activated the calcium signaling in FY subcutaneous fat, followed by the increase of adipocyte secretion, and resulted in more leptin (LEP) secretion (p < 0.01). Then peroxisome proliferator-activated receptor (PPAR) signaling was activated by the focal adhesions and ECM–receptor interaction. Finally, the TG and steroid synthesis increased by the expression regulation of ME1, SCD, ELOVL6, DGAT2, DBI, LPL, CPT1, PLIN1, LIPA, DHCR24, and SQLE gene. The above genes can be considered as the candidate genes for yak with higher fat amount in molecular breeding in the future. This study can provide a theoretical basis for improving the meat quality and breeding of yaks.

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Physiologic and Pharmacologic Modulation of Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Expression in -Cells by Peroxisome Proliferator-Activated Receptor (PPAR)- Signaling: Possible Mechanism for the GIP Resistance in Type 2 Diabetes

Diabetes ◽

10.2337/db09-1655 ◽

2010 ◽

Vol 59 (6) ◽

pp. 1445-1450 ◽

Cited By ~ 34

Author(s):

D. Gupta ◽

M. Peshavaria ◽

N. Monga ◽

T. L. Jetton ◽

J. L. Leahy

Keyword(s):

Type 2 Diabetes ◽

Receptor Expression ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Signaling ◽

Pharmacologic Modulation ◽

Gip Receptor ◽

In Cells

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Evidence for the Regulatory Role of Lipocalin 2 in High-Fat Diet-Induced Adipose Tissue Remodeling in Male Mice

Endocrinology ◽

10.1210/en.2013-1289 ◽

2013 ◽

Vol 154 (10) ◽

pp. 3525-3538 ◽

Cited By ~ 33

Author(s):

Hong Guo ◽

Merlijn Bazuine ◽

Daozhong Jin ◽

Merry M. Huang ◽

Samuel W. Cushman ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Adipocyte Differentiation ◽

Tissue Remodeling ◽

Peroxisome Proliferator ◽

Lipocalin 2 ◽

Peroxisome Proliferator Activated Receptor ◽

Adipose Tissue Remodeling ◽

Fat Depot

Lipocalin 2 (Lcn2) has previously been characterized as an adipokine/cytokine playing a role in glucose and lipid homeostasis. In this study, we investigate the role of Lcn2 in adipose tissue remodeling during high-fat diet (HFD)-induced obesity. We find that Lcn2 protein is highly abundant selectively in inguinal adipose tissue. During 16 weeks of HFD feeding, the inguinal fat depot expanded continuously, whereas the expansion of the epididymal fat depot was reduced in both wild-type (WT) and Lcn2−/− mice. Interestingly, the depot-specific effect of HFD on fat mass was exacerbated and appeared more pronounced and faster in Lcn2−/− mice than in WT mice. In Lcn2−/− mice, adipocyte hypertrophy in both inguinal and epididymal adipose tissue was more profoundly induced by age and HFD when compared with WT mice. The expression of peroxisome proliferator-activated receptor-γ protein was significantly down-regulated, whereas the gene expression of extracellular matrix proteins was up-regulated selectively in epididymal adipocytes of Lcn2−/− mice. Consistent with these observations, collagen deposition was selectively higher in the epididymal, but not in the inguinal adipose depot of Lcn2−/− mice. Administration of the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (Rosi) restored adipogenic gene expression. However, Lcn2 deficiency did not alter the responsiveness of adipose tissue to Rosi effects on the extracellular matrix expression. Rosi treatment led to the further enlargement of adipocytes with improved metabolic activity in Lcn2−/− mice, which may be associated with a more pronounced effect of Rosi treatment in reducing TGF-β in Lcn2−/− adipose tissue. Consistent with these in vivo observations, Lcn2 deficiency reduces the adipocyte differentiation capacity of stromal-vascular cells isolated from HFD-fed mice in these cells. Herein Rosi treatment was again able to stimulate adipocyte differentiation to a similar extent in WT and Lcn2−/− inguinal and epididymal stromal-vascular cells. Thus, combined, our data indicate that Lcn2 has a depot-specific role in HFD-induced adipose tissue remodeling.

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Abstract 290: Proliferation of Cardiac Fibroblasts Defines Early Stages of Genetic Dilated Cardiomyopathy and Precedes Myocardial Metabolic Derangement

Circulation Research ◽

10.1161/res.115.suppl_1.290 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Michael A Burke ◽

Stephen Chang ◽

Danos C Christodoulou ◽

Joshua M Gorham ◽

Hiroko Wakimoto ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Fibroblasts ◽

Expression Patterns ◽

Molecular Networks ◽

Peroxisome Proliferator ◽

Metabolic Derangement ◽

Peroxisome Proliferator Activated Receptor ◽

Cell Remodeling ◽

Ppar Signaling ◽

Myocyte Proliferation

The complex molecular networks underpinning DCM remain poorly understood. To study distinct pathways and networks in the longitudinal development of DCM we performed RNAseq on LV tissue from mice carrying a human DCM mutation in phospholamban (PLN R9C/+ ) before phenotype onset (pre-DCM), with DCM, and during overt heart failure (HF), and also on isolated myocytes and non-myocytes from DCM hearts. PLN R9C/+ mice show progressive fibrosis (20% vs. 1% control, p=6x10 −33 ; n=3) associated with proliferation of cardiac non-myocytes (33% increase over control, p=6x10 −4 ; n=3). Consistent with this, cardiac non-myocytes have upregulated gene expression and pathways, while these are generally downregulated in myocytes. Non-myocytes were enriched in fibrosis, inflammation, and cell remodeling pathways, from pre-DCM to HF. In contrast, myocytes were enriched for metabolic pathways only with overt DCM and HF. Myocytes showed profound derangement of oxidative phosphorylation with DCM (p=2.5x10 −41 ; 44% (53/120) of pathway genes downregulated), suggesting mitochondrial dysfunction. Additionally, we detected probable inhibition of peroxisome proliferator-activated receptor (PPAR) signaling by diminished expression of pathway genes (Figure). DCM and hypertrophic remodeling was compared using RNAseq of a mouse model of HCM; similar patterns of fibrosis with myocyte metabolic dysregulation were evident despite unique differential gene expression patterns between models. DCM caused by PLN R9C/+ is associated with early non-myocyte proliferation and later myocyte metabolic derangement possibly governed by altered PPAR signaling, and is common to DCM and HCM.

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Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Biomedicines ◽

10.3390/biomedicines9111647 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1647

Author(s):

Keishi Kisoh ◽

Go Sugahara ◽

Yuko Ogawa ◽

Suzue Furukawa ◽

Yuji Ishida ◽

...

Keyword(s):

Drug Development ◽

Drug Efficacy ◽

Developed Countries ◽

Liver Disorder ◽

New Drugs ◽

Peroxisome Proliferator ◽

Chimeric Mice ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver ◽

Nash Model

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.

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The RNA degradation pathway is involved in PPARα-modulated anti-oral tumorigenesis

BioMedicine ◽

10.1051/bmdcn/2019090427 ◽

2019 ◽

Vol 9 (4) ◽

pp. 27

Author(s):

Nai-Wen Chang ◽

Yi-Ping Huang

Keyword(s):

Oral Cancer ◽

Enrichment Analysis ◽

Rna Degradation ◽

Degradation Pathway ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

New Strategy ◽

Tramp Complex ◽

Oral Cancer Cells ◽

Next Generation Sequencing Ngs

Background: The activation of peroxisome proliferator-activated receptor alpha (PPARα) has been shown to reprogram tumor metabolism and exhibits great potential for treating anti-oral tumorigenesis. Methods: In this study, we used a pathway-based strategy to explore possible functional pathways involved in the anticancer activity of PPARα in oral cancer cells through next-generation sequencing (NGS) and bioinformatic approaches. Results: We found that 3919 genes were upregulated and 1060 genes were downregulated through PPARα activation. These genes were mainly involved in the proteasomal, mRNA surveillance, spliceosomal, RNA transport, and RNA degradation pathways, as indicated by GO and KEGG enrichment analysis. Importantly, a total of 13 upregulated genes in the RNA degradation pathway were identified including 3 core exosome factor genes (RRP43, RRP42, and CSL4), 2 TRAMP complex genes (TRF4 and Mtr4), 2 exosome cofactor genes (RRP6 and MPP6), 2 CCR4-NOT complex genes (CNOT2 and CNOT3), 2 Ski complex genes (SKI2 and Ski3), 1 decapping complex gene (EDC4), and 1 gene involved in 5’ exoribonuclease activity (XRN1). Conclusion: Our findings suggest that the activation of PPARα to upregulate the RNA degradation pathway might provide a new strategy for oral cancer treatment.

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