Search Results (51)

Adipogenic differentiation is essential for adipose tissue development, fat deposition, and metabolic regulation in livestock, but the role of RNA-binding proteins in sheep preadipocyte differentiation remains unclear. This study investigated whether Quaking (QKI) regulates sheep preadipocyte adipogenesis and explored its downstream regulatory mechanism. QKI expression was examined in sheep adipose tissues, and QKI knockdown was performed in sheep preadipocytes. Adipogenic marker expression, lipid accumulation, glucose consumption, Oxford Nanopore Technologies (ONT) full-length transcriptome sequencing, RNA immunoprecipitation coupled with quantitative real-time PCR (RIP-qPCR), actinomycin D assay, caveolae-associated protein 3 (Cavin3) knockdown, and simultaneous QKI and Cavin3 knockdown were used to evaluate the function and mechanism of QKI. QKI was expressed in different sheep adipose tissues, with relatively higher expression in tail fat. QKI knockdown reduced adipogenic marker expression, Oil Red O staining, and glucose consumption after adipogenic induction. ONT full-length transcriptome sequencing identified Cavin3 as a markedly upregulated candidate downstream target after QKI knockdown. RIP-qPCR showed enrichment of Cavin3 mRNA in QKI immunoprecipitates, and actinomycin D assays indicated that QKI knockdown delayed Cavin3 mRNA degradation. Cavin3 knockdown enhanced adipogenic marker expression, Oil Red O staining, and glucose consumption. Simultaneous QKI and Cavin3 knockdown increased adiponectin, fatty-acid-binding protein 4, and peroxisome proliferator-activated receptor gamma mRNA abundance and Oil Red O staining relative to the matched control, whereas glucose consumption was not significantly different. These findings suggest that QKI promotes sheep preadipocyte differentiation, at least in part, by reducing Cavin3 mRNA stability, providing insight into RNA-binding protein-mediated regulation of livestock adipogenesis. Full article

Background: Adult-onset recessive cerebellar ataxias remain frequently unresolved after next-generation sequencing, partly because phenotype-driven filtering can deprioritize biallelic variants in genes historically associated with severe pediatric multisystem disease. This review examines how attenuated, hypomorphic, or residual-function genotypes may present as late-onset, cerebellar-predominant disease and aims to support clinical interpretation of apparently discordant recessive findings. Methods: We performed a narrative, pathway-based synthesis of autosomal recessive adult- or late-onset ataxia involving genes classically linked to lysosomal/neuronal ceroid lipofuscinosis and peroxisomal disorders. Reports were assessed for age at onset, cerebellar and extracerebellar chronology, variant class, zygosity, segregation/in-trans confirmation, biochemical or functional evidence, and implications for clinician–laboratory interpretation. Results: Published reports indicate that selected NCL-related and peroxisomal genes may be clinically relevant in adult-onset cerebellar ataxia, especially when accompanied by retinal disease, hearing loss, neuropathy, cognitive or psychiatric features, epilepsy/myoclonus, movement-disorder signs, or subtle biochemical abnormalities. Apparent phenotype–gene discordance may be compatible with residual function, allelic-series effects, and cerebellar selective vulnerability, although evidence is often limited to case reports or small series with variable segregation, biochemical, and functional support. We propose a workflow based on structured phenotype transfer, in-trans confirmation, targeted re-phenotyping, ACMG/AMP-informed evidence weighting, and avoidance of label-based exclusion from “ataxia gene” lists. Conclusions: Adult-onset recessive ataxia should not be interpreted only through canonical pediatric disease labels. A pathway-aware, phenotype-complete approach may reduce avoidable VUS retention and improve recognition of attenuated genetic presentations. Full article

Hypertriglyceridemic acute pancreatitis (HTG-AP) progresses rapidly with poor prognosis. Intestinal barrier dysfunction and excessive oxidative stress contribute to its pathogenesis, but specific mediators linking gut injury, oxidative stress and pancreatic damage remain unclear. Here, we identify endogenous phenyllactic acid (PLA) as a critical metabolite regulating intestinal barrier integrity and oxidative homeostasis in HTG-AP. We noted serum PLA, a disease-associated metabolite whose reduction correlates with gut dysbiosis and pancreatic inflammation in HTG-AP. PLA supplementation in HTG-AP mice attenuated intestinal barrier dysfunction and mitigated intestinal oxidative stress, as evidenced by improved gut dysbiosis, reduced reactive oxygen species accumulation, restored superoxide dismutase activity, restored barrier integrity, reduced bacterial translocation to the pancreas, and decreased serum lipopolysaccharide levels, ultimately mitigating pancreatic injury. RNA sequencing of colonic tissue revealed peroxisome proliferator-activated receptor (PPAR) signaling as one of the most significantly altered pathways in HTG-AP. PPARγ expression was markedly reduced in colonic epithelial cells and upregulated upon PLA treatment. Knockdown of colonic epithelial PPARγ via adeno-associated virus abrogated the beneficial effects of PLA on intestinal barrier integrity, oxidative stress and pancreatic injury in HTG-AP mice. The protective effects of PLA were phenocopied by the PPARγ agonist rosiglitazone. Collectively, these findings identified gut microbiota-derived PLA as an endogenously derived metabolite modulating intestinal oxidative stress and barrier function. Using male C57BL/6J mice to establish an HTG-AP model, we further revealed that PLA exerts protective effects against HTG-AP by targeting colonic PPARγ to modulate the gut–pancreas axis, highlighting PLA as a promising candidate for targeted intervention in HTG-AP. Full article

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

Seed aging is a critical biological process that leads to progressive loss of seed vigor, thereby constraining germplasm conservation and agricultural productivity. To elucidate the molecular mechanisms underlying this process in grass species, we performed transcriptomic analyses to characterize regulatory networks underlying seed aging in Elymus sibiricus, a dominant forage species on the Qinghai–Tibet Plateau. Seeds were subjected to artificial accelerated aging (45 °C, 80% relative humidity, 1–6 days), followed by physiological evaluation and RNA sequencing. Seed vigor and germination percentage declined markedly with aging, accompanied by extensive transcriptional reprogramming. Integrative analyses identified pyruvate metabolism, MAPK signaling, and peroxisome function as key processes associated with vigor loss during late-stage aging. WGCNA further revealed that genes encoding heat shock proteins and glutathione metabolism-related enzymes were co-localized within the same module, suggesting a possible synergistic role in preserving seed viability during aging. In addition, WRKY24, ARF9, and ARF19 were identified as candidate hub transcription factors. WRKY24 may contribute to aging by modulating antioxidant defense-related genes (e.g., TRX1 and NRPC1), while ARF9 and ARF19 may regulate ROS homeostasis through predicted downstream targets, including FQR1, PER2, MAO1B, ANN5, and MT2B. Together, these findings support a hypothetical regulatory model in which WRKY and ARF transcription factors coordinate redox homeostasis and hormone signaling to regulate seed longevity in E. sibiricus. This study provides a systems-level framework for understanding seed aging in perennial grasses and identifies potential genetic targets for improving seed storability, with implications for germplasm conservation and alpine grassland sustainability. Full article

Acute kidney injury (AKI) is a major complication of lupus nephritis and kidney transplantation, inevitably causing ischemia–reperfusion (I/R) injury. We previously confirmed that high-dose voclosporin induces drug nephropathy through aberrant peroxisome accumulation. The latter induces increased renal indole-3-aceticT acid (IAA) production due to the decreased expression of the IAA-degrading enzyme indolethylamine N-methyltransferase (INMT). Conversely, INMT overexpression prevents this nephropathy, suggesting that high-dose voclosporin could enable a novel therapeutic approach. This prompted us to test whether INMT overexpression with high-dose voclosporin could avert nephrotoxicity and protect against I/R injury. Inmt-overexpressing mice treated with high-dose voclosporin exhibited absence of peroxisomal abnormalities and resistance to I/R injury. RNA sequencing revealed the downregulation of tubular injury markers NGAL (Lcn2) and KIM-1 (Havcr1) concurrent with significant cytokine suppression. Mechanistic analysis revealed the robust induction of Regnase-2, an mRNA decay factor, which directly targeted stem–loop structures within the 3′ untranslated region of Lcn2 and Havcr1, thereby promoting their degradation in proximal tubular cells. Importantly, Regnase-2 knockdown mice showed Lcn2 upregulation, mitochondrial dysfunction, and peroxisomal abnormalities culminating in AKI, underscoring its renal protective effects. High-dose voclosporin under Inmt overexpression promoted Regnase-2-mediated mRNA decay to suppress tubular injury. This protective effect extended beyond I/R to rhabdomyolysis- and lipopolysaccharide-induced AKI to prevent nephropathy. Our findings demonstrate the potential transformative therapeutic approach of administering high-dose voclosporin to promote the prophylactic effect of Regnase-2 augmentation against AKI in both native and transplanted human kidneys. Full article

Piglets weaning is a critical developmental stage marked by significant metabolic and inflammatory challenges. The hepatic responses during this period may differ among pig breeds with distinct genetic backgrounds. To explore the phenotypic and molecular differences in the livers between the Zaozhuang Heigai (HG) pig and Duroc×Landrace×Yorkshire (DLY) piglets and elucidate the regulatory mechanisms of genetic background on liver function, five 35-day-old piglets from each breed were selected. Body weight and liver coefficients were measured; histological features of liver sections were observed, and the transcriptome and metabolome of the liver were determined using mRNA sequencing and non-targeted metabolomics analysis. The results showed that HG piglets had significantly lower body weight (p < 0.01) and slightly higher liver coefficients than DLY piglets. Histological examination revealed that the hepatic lobule structure was intact in both breeds, while mild hepatic congestion was observed in some DLY piglets. Transcriptome analysis identified 429 differentially expressed genes (DEGs) with criteria of FDR adjusted p-values < 0.01 and |log₂(Fold Change)| > 1, and they were significantly enriched in oxidoreductase activity, peroxisome proliferator-activated receptor (PPAR) signaling, and arachidonic acid metabolism pathways. Metabolome analysis identified 169 differentially expressed metabolites (DEMs) with criteria of p < 0.05, VIP > 1, and |log₂(Fold Change)| > 1, and they were significantly enriched in nucleotide metabolism, arginine biosynthesis, and arachidonic acid metabolism pathways. Integrative analysis of DEGs and DEMs showed that arachidonic acid metabolism was the common pathway. Within this pathway, key genes (GPX3, ALOX5, and CBR3) were significantly associated with specific metabolites (15-deoxy-PGJ₂ and phosphatidylcholines) (FDR adjusted p < 0.05), suggesting a gene–metabolite interaction network that coordinates inflammatory regulation and oxidative stress. These findings provide molecular evidence for breed-specific hepatic metabolic regulation during the weaning period and are therefore conducive to the management of weaned piglets and the investigation of local pig characteristics. Full article

This study investigated the molecular and microbial factors behind the higher disease resistance of hybrid taimen by combining gut microbiome profiling with host transcriptomic analysis of intestinal and liver tissues. Both hybrid taimen and H. taimen were raised under the same recirculating aquaculture system (RAS) conditions. After recording survival rates following three enteritis outbreaks, samples of intestinal contents and tissues were collected from both groups. The gut microbiota was analyzed using full-length 16S rRNA sequencing in PacBio, and host gene expression was assessed with Illumina RNA-seq. Functional predictions were made using PICRUSt2 and Gene Set Enrichment Analysis (GSEA). Results showed that hybrids had significantly higher survival rates after enteritis (p < 0.05). Although microbial alpha diversity was similar, beta diversity revealed slight compositional differences. Hybrids showed higher levels of Hapalosiphon and Tepidimicrobium, microbes associated with antimicrobial compounds and the metabolism of short-chain fatty acids (SCFAs). Functional predictions indicated enrichment in selenocompound metabolism and ansamycin biosynthesis in hybrids. Transcriptomic analysis identified 4233 differentially expressed genes (DEGs) in the intestine and 3980 in the liver. In hybrids, intestinal tissues exhibited increased expression of immune pathways, including complement activation, lysosomal activity, and the transforming growth factor-beta (TGF-β) signaling pathway. Liver tissues demonstrated higher expression of genes related to cholesterol synthesis, fatty acid degradation, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. qRT-PCR validated the expression patterns of 20 selected DEGs. These findings tentatively suggest that the elevated disease resistance of hybrid taimen may be linked, at least in part, to a combination of microbial taxa inferred to produce antimicrobial metabolites and short-chain fatty acids, as well as an apparent intensification of intestinal immune and barrier-related gene expression, and hepatic pathways that possibly support energy supply and steroid-based immunity. However, this multi-omics data set is only correlational. We still do not know whether a single strain or a few host genes are enough to produce the resistant phenotype. Gnotobiotic trials, microbiota transplants, and targeted metabolomics will be necessary to turn these interesting associations into solid evidence. Full article

Long non-coding RNAs (lncRNAs) are crucial regulators in eukaryotic organisms, yet their roles in filamentous fungi, particularly in environmental adaptation and metabolic changes, remain largely unexplored. Here, we investigated the roles of lncRNAs in salt stress response, morphological differentiation, and metabolic regulation in Eurotium cristatum. Using strand-specific RNA sequencing, we identified lncRNAs in sexual and asexual mycelia of E. cristatum and analyzed their expression profiles. We identified 203 lncRNAs, with 120 significantly differentially expressed (FDR < 0.01; |log₂ (fold change)| ≥ 1) under salt stress, including 57 upregulated and 63 downregulated in the asexual morph compared to the sexual morph. These lncRNAs correlated with physiological indicators like mycelial biomass, polysaccharide content, and melanin production. Target gene prediction and functional enrichment analysis revealed that these lncRNAs influenced morphogenesis and secondary metabolite synthesis in E. cristatum by regulating pathways including carbohydrate metabolism, peroxisome function, and protein ubiquitination. The lncRNA MSTRG.10627.3 showed the highest upregulation (log₂FC = 10.53, FDR < 1 × 10⁻¹⁰⁵), while MSTRG.3124.1 was significantly downregulated in the sexual morph (log₂FC = −4.94, FDR < 1 × 10⁻⁸⁸). A regulatory network of lncRNAs involved in salt stress responses was constructed, providing insights into fungal environmental adaptation mechanisms and potential targets for industrial strain improvement. Full article

This study aimed to elucidate the role of peroxisome proliferator-activated receptor-γ (PPAR-γ) in regulating macrophage efferocytosis during the pathogenesis of chronic apical periodontitis (CAP). Clinical specimens, rat periapical lesion models, and an in vitro model simulating the CAP inflammatory milieu were employed to examine the contribution of PPAR-γ to efferocytosis throughout disease progression. The expression of PPAR-γ in vivo was assessed by single-cell RNA sequencing and immunohistochemical (IHC) staining. Pearson’s correlation and linear trend tests were conducted to investigate the association between PPAR-γ and macrophage efferocytosis during CAP progression. Pharmacological modulation of PPAR-γ was further conducted using rosiglitazone (RSG) as an agonist and GW9662 as an antagonist, followed by an assessment of efferocytosis-related parameters and inflammatory responses. Both clinical specimens and animal models demonstrated a progressive reduction in PPAR-γ expression and macrophage efferocytosis during CAP. Notably, PPAR-γ attenuated efferocytosis impairment and significantly reduced pathogen-induced inflammatory responses in macrophages. These findings indicate that defective macrophage efferocytosis contributes to the exacerbation of CAP severity, whereas targeting PPAR-γ may represent a promising therapeutic strategy to alleviate inflammation in periapical lesions by restoring efferocytic capacity. Collectively, this study highlights PPAR-γ as a potential therapeutic target warranting further investigation in CAP treatment. Full article

Autism Spectrum Disorder (ASD) is a complex and multifactorial neurodevelopmental condition whose pathogenesis remains only partially elucidated. Earlier accounts of oxidative stress in ASD often relied on the reductive paradigm of an imbalance between oxidants and antioxidants. In contrast, this narrative review, based on a systematic examination of 1102 publications indexed in scientific databases from 2002 to July 2025, reframes the discussion in terms of redox system dysfunction, a broader and more integrative construct. Here, reactive oxidant species, molecular targets, and reducing/antioxidant counterparts are considered elements of a dynamic circuitry whose maladaptation progressively undermines homeostasis. The sequence of events unfolds in three stages. The first is primary redox dysfunction, manifesting as alterations in metabolic, signaling, and defense pathways. From this disturbance, a second stage arises, marked by functional derailment of cellular compartments—from membranes and cytosol to organelles and nuclei—including mitochondrial and peroxisomal deficits. Ultimately, a third stage emerges, defined by neurodevelopmental alterations such as impaired neurotransmission, synaptic dysfunction, abnormal plasticity, morphogenetic defects, neuroinflammation, and gut–brain–microbiota disarrangements. This progression situates the redox system as a central hub at the interface between human cells and the microbiota, resonating with the ecological and evolutionary principles of the holobiont and the One Health framework. By weaving dispersed evidence into a coherent perspective, this review advances beyond previous analyses, offering a unifying paradigm that connects biochemical dysfunction to clinical heterogeneity in ASD and opens new directions for interdisciplinary research. Full article

The overdose of acetaminophen (APAP) has become the leading cause of acute liver failure in the United States and some Western countries. As a principal member of the cytochrome P450 enzymes (CYPs), CYP2E1 is a vital enzyme in regard to the production of toxic APAP metabolites and in the development of APAP-induced liver injury (AILI). In this study, we investigated the therapeutic effects and mechanisms of lipid nanoparticle (LNP)-based delivery of small interfering RNA targeting Cyp2e1 (si-Cyp2e1 LNPs) on AILI in mice. C57BL/6J male mice were injected with 300 mg/kg APAP to establish an AILI model, and si-Cyp2e1 LNPs were administered via the tail vein. The results showed that the levels of serum alanine aminotransferase and aspartate aminotransferase were lower than those in APAP mice after treatment with si-Cyp2e1 LNPs immediately. Moreover, si-Cyp2e1 LNPs significantly inhibited liver necrosis and oxidative stress in APAP mice. RNA sequencing revealed that si-Cyp2e1 LNPs exerted regulatory effects on pathways and genes related to peroxisome proliferator-activated receptor (PPAR). Consistent with this finding, we also proved that si-Cyp2e1 LNPs markedly regulated the expressions of genes involved in the PPAR signaling pathway (CYP4A, PPARα, FABP 1, and CD36) in APAP mice, as well as inflammatory factors (Il-6, Il-1β, and Tnf-α). These findings suggested that si-Cyp2e1 LNPs may alleviate APAP-induced oxidative stress and inflammation by regulating lipid metabolism via PPAR-related pathways. Full article

Thyroid hormone (TH) plays a vital role in ovarian follicle development, and glucose-regulated protein 78 (GRP78) is involved in these processes, which is regulated by TH. However, the mechanisms are still unclear. To evaluate the possible mechanism of TH on the regulation of GRP78 expression, Cleavage Under Targets and Tagmentation (CUT & Tag) sequencing, luciferase assays, and Electrophoretic Mobility Shift Assays (EMSA) were employed to delineate the binding sites of thyroid hormone receptor β (TRβ) on the GRP78 promoter and to confirm the interactions. Additionally, Co-Immunoprecipitation (Co-IP) and Immunofluorescence (IF) assays were used to investigate the interactions between TRβ and the coactivator peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) after triiodothyronine (T₃) treatment with different concentrations. Our findings identified a thyroid hormone response element (TRE) on the GRP78 promoter and demonstrated that TRβ can activate GRP78 expression by interacting with PGC-1α. In order to simulate the condition of hyperthyroidism, granulosa cells (GCs) extracted from rats were treated by T₃ with high concentrations, which decreased the expression of PGC-1α, resulting in decreased expressions of GRP78 and other ferroptosis-related markers such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11, xCT), thereby inducing ferroptosis in GCs. Taken together, the present study demonstrates that T₃ induces cellular ferroptosis by binding TRE of the GRP78 promoter in ovarian GCs via TRβ. As a switcher, PGC-1α is also involved in these processes. Full article

Ischemic stroke is a leading cause of death and disability worldwide. Currently, there is an unmet clinical need for pharmacological treatments that can improve ischemic stroke outcomes. In this study, we investigated the role of brain peroxisome proliferator-activated receptor alpha (PPARα) in ischemic stroke pathophysiology. We used a well-established model of cerebral ischemia in PPARα transgenic mice and conducted the RNA sequencing (RNA-seq) of mouse stroke brains harvested 48 h post-middle cerebral artery occlusion (MCAO). PPARα knockout (KO) increased brain infarct size following stroke, indicating a protective role of PPARα in brain ischemia. Our RNA-seq analysis showed that PPARα KO altered the expression of genes in mouse brains with known roles in ischemic stroke pathophysiology. We also identified many other differentially expressed genes (DEGs) upon the loss of PPARα that correlated with increased infarct size in our stroke model. Gene set enrichment analysis (GSEA) and Gene Ontology (GO) analysis revealed the upregulation of gene signatures for the positive regulation of leukocyte proliferation, apoptotic processes, acute-phase response, and cellular component disassembly in mouse stroke brains with PPARα KO. In addition, pathway analysis of our RNA-seq data revealed that TNFα signaling, IL6/STAT3 signaling, and epithelial–mesenchymal transition (EMT) gene signatures were increased in PPARα KO stroke brains. Our study highlights PPARα as an attractive drug target for ischemic stroke due to its transcriptional regulation of inflammation-, apoptosis-, and EMT-related genes in brain tissue following ischemia. Full article

To elucidate the unidentified roles of a selective peroxisome proliferator-activated receptor α (PPARα) agonist, pemafibrate (Pema), on the pathogenesis of retinal ischemic diseases (RID)s, the pharmacological effects of Pema on the retinal pigment epithelium (RPE), which is involved in the pathogenesis of RID, were compared with the pharmacological effects of the non-fibrate PPARα agonist GW7647 (GW). For this purpose, the human RPE cell line ARPE19 that was untreated (NT) or treated with Pema or GW was subjected to Seahorse cellular metabolic analysis and RNA sequencing analysis. Real-time cellular metabolic function analysis revealed that pharmacological effects of the PPARα agonist actions on essential metabolic functions in RPE cells were substantially different between Pema-treated cells and GW-treated cells. RNA sequencing analysis revealed the following differentially expressed genes (DEGs): (1) NT vs. Pema-treated cells, 37 substantially upregulated and 72 substantially downregulated DEGs; (2) NT vs. GW-treated cells, 32 substantially upregulated and 54 substantially downregulated DEGs; and (3) Pema vs. GW, 67 substantially upregulated and 51 markedly downregulated DEGs. Gene ontology (GO) analysis and ingenuity pathway analysis (IPA) showed several overlaps or differences in biological functions and pathways estimated by the DEGs between NT and Pema-treated cells and between NT and GW-treated cells, presumably due to common PPARα agonist actions or unspecific off-target effects to each. For further estimation, overlaps of DEGs among different pairs of comparisons (NT vs. Pema, NT vs. GW, and Pema vs. GW) were listed up. Angiopoietin-like 4 (ANGPTL4), which has been shown to cause deterioration of RID, was the only DEG identified as a common significantly upregulated DEG in all three pairs of comparisons, suggesting that ANGPTL4 was upregulated by the PPARα agonist action but that its levels were substantially lower in Pema-treated cells than in GW-treated cells. In qPCR analysis, such lower efficacy for upregulation of the mRNA expression of ANGPTL4 by Pema than by GW was confirmed, in addition to substantial upregulation of the mRNA expression of HIF1α by both agonists. However, different Pema and GW-induced effects on mRNA expression of HIF1α (Pema, no change; GW, significantly downregulated) and mRNA expression of ANGPTL4 (Pema, significantly upregulated; GW, significantly downregulated) were observed in HepG2 cells, a human hepatocyte cell line. The results of this study suggest that actions of the PPARα agonists Pema and GW are significantly organ-specific and that lower upregulation of mRNA expression of the DR-worsening factor ANGPTL4 by Pema than by GW in ARPE19 cells may minimize the risk for development of RID. Full article