PPARγ Signaling Research Articles

TRIB3 suppresses milk fatty acids metabolism by inhibiting p‐AKT/PPARG signaling in goat mammary epithelial cells

AbstractTribbles pseudokinase 3 (TRIB3) interacts with a variety of proteins and plays a key role in the regulation of glucose metabolism and glycolysis in nonruminants, but whether it has a specific role in goat mammary lipid metabolism has still been kept unknown. In this study, we observed that TRIB3 is highly expressed in the mammary tissues of lactating dairy goats. Overexpressing TRIB3 in goat mammary epithelial cells (GMECs) suppressed the mRNA expression of GPAM, DGAT1, and PLIN1, which are associated with the formation of triacylglycerol and lipid droplets (p < 0.05). The fatty acid‐sensitive transcription regulator PPARG was also downregulated. Interfering TRIB3 had the opposite effect and decreased Akt phosphorylation. The TRIB3 gene influenced fatty acid composition in GMECs, and its overexpression reduced the total concentration of intracellular triacylglycerol (p < 0.01), this response was verified using BODIPY staining. Overall, these data indicated that TRIB3 suppresses milk fatty acids metabolism through inhibiting p‐AKT/PPARG signaling in GMECs.

Gut-derived PPAR-γ signaling and risk of bacterial enteric infection: insight from thiazolidinedione users in a US population-based study.

Background and Aims The ongoing antimicrobial resistant crisis heralds the need for new therapeutics against enteric infection. In mouse models, colon epithelial peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling limits oxygen and nitrate luminal bioavailability, thereby preventing bacterial pathogen colonization. However, whether this mechanism operates similarly in humans remains uncertain. Methods To investigate, we used the cloud-based TriNetX Analytics Platform which aggregates health records from 117 million patients across 66 US healthcare organizations, to assess the risk of bacterial enteric infection among diabetic patients prescribed thiazolidinediones, a class of PPAR-γ agonists, to other anti0diabetes medications/ . Results Among 85,117 thiazolidinedione users, we observed a 22-49% lower risk of bacterial enteric infections compared to users of other anti-diabetes medications. This reduction in risk was consistent across high-risk individuals, regardless of sex or age. Similar results were replicated in high-risk patients when thiazolidinedione users were directly compared to those on DPP-4 inhibitors. Conclusion These findings support the potential protective role of PPAR-γ signaling against bacterial enteric infection and call for further clinical investigation.

Scopoletin: A Validated Protector against Cerulein-induced Acute Pancreatitis & Associated Lung Injury by Regulating PPAR- γ "A Multidimensional Approach".

Our previous study established the effectiveness of scopoletin (SC) in protecting mice against acute pancreatitis (AP) induced by cerulein and subsequent pulmonary injury. However, the precise molecular mechanisms underlying SC protective effects have yet to be elucidated. This research suggests that SC reduces the release of pro-inflammatory cytokines and nuclear factor kappa B (NF-κB) by activating the peroxisome proliferator-activated receptor γ (PPAR-γ) in mice suffering from AP. We observed the protective role of SC against the male Swiss mice with hourly intraperitoneal injections of cerulein (50µg/kg) for six hours, followed by the administration of SC (10mg/kg) one hour after AP induction, with or without the PPAR-γ antagonist GW9662 (0.3mg/kg). The study exploration into the anti-inflammatory effects of SC revealed that a concentration of 25µM enhanced the phagocytic clearance of dying pancreatic acinar cells by triggering the PPAR-γ signaling activation. Conversely, an in vitro assessment confirmed the presence of GW9662 counteracted the beneficial impact of SC on acinar cells. Molecular docking and simulation studies have shown that SC prompts significant structural changes in PPAR-γ. The in vivo, in vitro, and in silico analyses suggest that SC has potent anti-inflammatory properties that may be mediated by the activation of PPAR-γ signaling in cerulein-induced experimental pancreatitis.

FABP4 Inhibitor Alleviates Lipopolysaccharide-Induced HUVEC Injury by Inactivating NF-κB and Activating PPARγ.

The study aims to examine the effect of FABP4 on inflammatory response and angiogenesis in the cell model of atherosclerosis and to explore its potential mechanism.Using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, the mRNA and protein levels of FABP4 in human umbilical vein endothelial cells (HUVECs) treated with lipopolysaccharide (LPS) or oxidized low-density lipoprotein for 6, 12, 24, or 48 hours were measured. To silence FABP4 expression and NF-κB signaling in HUVECs, FABP4 inhibitor and NF-κB inhibitor were utilized. To assess cell survival rate and apoptosis, methyl thiazolyl tetrazolium assays and flow cytometry analysis were conducted. Genes related to cholesterol metabolism, including LOX-1, ABCA1, and ABCG1, were subjected to RT-qPCR and western blotting. Moreover, protein levels of apoptotic markers (Bcl-2 and Bax), PPARγ, the phosphorylated levels of NF-κB p65, and angiogenetic markers (ICAM1, VCAM1, and VEGF) were quantified via western blotting. Using an enzyme-linked immunosorbent assay, concentrations of inflammatory cytokines in HUVECs were measured.FABP4 expression was upregulated in LPS-stimulated HUVECs. The silencing of FABP4 lowered LOX-1 and p65 levels while upregulating ABCA1 and ABCG1 expression in the context of LPS. Furthermore, the inhibition of FABP4 or NF-κB signaling promoted the growth of HUVECs, upregulated Bcl-2 and PPARγ protein levels, and reduced Bax levels, angiogenetic markers, and inflammatory cytokines in the context of LPS. The combination of FABP4 inhibitor and NF-κB inhibitor treatment amplified the above-mentioned effects on cell growth, angiogenesis, and inflammation.Inhibition of FABP4 reduces LPS-induced HUVEC cell damage via the inactivation of NF-κB p65 and activation of PPARγ signaling.

Slow Metabolism-Driven Amplification of Hepatic PPARγ Agonism Mediates Benzbromarone-Induced Obesity-Specific Liver Injury.

Obesity and nonalcoholic fatty liver disease (NAFLD) are established risk factors for drug-induced liver injury (DILI). The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti-gout/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity-specific DILI warrants further investigation. In this study, through a combined multi-omics, pharmacological, and pharmacokinetic approaches, it is found that BBR-induced obesity-specific DILI is primarily through the potentiation of peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db/db mice exhibited a diminished capacity to metabolize BBR in their livers. This reduction leads to prolonged retention of BBR, subsequently resulting in chronic and sustained hepatic PPARγ agonism. This study demonstrates that a slow metabolism-driven amplification of hepatic PPARγ agonism mediates BBR-induced obesity-specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre-existing NAFLD in both clinical practice and drug discovery processes.

Anti-b diminishes hyperlipidaemia and hepatic steatosis in hamsters and mice by suppressing the mTOR/PPARγ and mTOR/SREBP1 signalling pathways.

As a chronic metabolic syndrome, hyperlipidaemia is manifested as aberrantly elevated cholesterol and triglyceride (TG) levels, primarily attributed to disorders in lipid metabolism. Despite the promising outlook for hyperlipidaemia treatment, the need persists for the development of lipid-lowering agents with heightened efficiency and minimal toxicity. This investigation aims to elucidate the lipid-lowering effects and potential pharmacodynamic mechanisms of Anti-b, a novel low MW compound. We employed high-fat diet (HFD) in hamsters and mice or oleic acid (OA) in cultures of HepG2 cells and LO2 cells to induce hyperlipidaemia models. We administered Anti-b to assess its therapeutic effects on dyslipidaemia and hepatic steatosis. We used western blotting, RNA sequencing, GO and KEGG analysis, oil red O staining, along with molecular docking and molecular dynamics simulation to elucidate the mechanisms underlying the effects of Anti-b. Anti-b exhibited a substantial reduction in HFD-induced elevation of blood lipids, liver weight to body weight ratio, liver diameter and hepatic fat accumulation. Moreover, Anti-b demonstrated therapeutic effects in alleviating total cholesterol (TC), TG levels, and lipid accumulation derived from OA in HepG2 cells and LO2 cells. Mechanistically, Anti-b selectively bound to the mTOR kinase protein and increased mTOR thermal stability, resulting in downregulation of phosphorylation level. Notably, Anti-b exerted anti-hyperlipidaemia effects by modulating PPARγ and SREBP1 signalling pathways and reducing the expression level of mSREBP1 and PPARγ proteins. In conclusion, our study has provided initial data of a novel low MW compound, Anti-b, designed and synthesised to target mTOR protein directly. Our results indicate that Anti-b may represent a novel class of drugs for the treatment of hyperlipidemia and hepatic steatosis.

Luteolin modulates macrophage phenotypic switching via the AMPK-PPARγ pathway to alleviate ulcerative colitis in mice

Ethnopharmacological relevanceLonicerae japonicae flos (LJF), the dried flower bud or newly bloomed flower of Lonicera japonica Thunb., is widely used in Traditional Chinese medicine (TCM), exhibiting anti-inflammatory and immune-enhancing properties. Luteolin (Lut) is a major bioactive component of LJF, demonstrating a regulatory role in immune disorders. However, the specific role of Lut in regulating macrophage-mediated intestinal inflammation and its underlying molecular mechanisms have not yet been fully explored.Aim of the study: This study was designed to explore whether Lut alleviates Ulcerative colitis (UC) in mice and to elucidate its underlying mechanism in intestinal inflammation. Materials and methodsMice were administered Dextran sodium sulfate (DSS) for 7 d to establish a UC model, followed by oral administration of Lut (12.5, 25, and 50 mg/kg body weight). RNA-sequencing (RNA-Seq) was used to screen signaling pathways. RAW264.7 cells were cultured and treated with Lut (6.25, 12.5, and 25 μM) and lipopolysaccharide (LPS, 1 μg/mL) for 24 h. To examine the role of the AMP-activated protein kinase (AMPK)/Peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, the cells were treated with compound C (an AMPK inhibitor) and GW9662 (a PPARγ antagonist). ResultsLut suppressed the inflammation of DSS-induced colitis in vivo, attenuated DSS-induced clinical man-ifestations, reversed colon length reduction, and reduced histological injury. Lut induced a shift in the macrophage phenotype from classical (M1) to alternative (M2) by suppressing M1 marker gene expression and enhancing M2 marker gene expression following DSS or LPS induction. RNA-seq revealed that PPARγ was involved in the regulation of macrophages by Lut. Furthermore, the polarization effect of Lut on macrophages was shown to be mediated through the AMPK-PPARγ signaling pathway. ConclusionThese findings indicate that Lut effectively ameliorates UC in mice through the activation of the AMPK-PPARγ signaling pathway, leading to the inhibition of macrophage M1 polarization and promotion of M2 polarization. This study provides insight into future research on the utilization of Lut-rich TCM dietary supplements as a prophylactic treatment strategy in the prevention of UC.

ASPP2 deficiency attenuates lipid accumulation through the PPARγ pathway in alcoholic liver injury

The initial stage of alcoholic liver disease (ALD) is hepatic steatosis. Recent studies have highlighted a possible role for Apoptosis-stimulating protein 2 of p53 (ASPP2) in regulating hepatic lipid metabolism in nonalcoholic fatty liver (NAFLD). However, whether ASPP2 regulates alcohol-induced lipid accumulation and its mechanisms remain unclear. To explore that, we establish an alcoholic liver injury model in vivo and in vitro. The clinical specimens were collected from liver tissues of patients with alcoholic liver disease. Lipid metabolism was detected by HE staining, oil red O staining and qPCR; and ASPP2-peroxisome proliferator-activated receptor γ (PPARγ) signaling pathways were detected by western blot and immunohistochemical staining. We found that both ASPP2 and PPARγ expression increased in patients and mouse models with ALD. We also discovered the reduction of ASPP2 significantly inhibited the expression of PPARγ and alleviated alcohol-induced hepatic lipid accumulation and liver injury in vivo and in vitro. Mechanistically, the PPARγ agonist reversed the protective effect of ASPP2 downregulation on hepatic steatosis and liver injury, while the opposite results were observed using PPARγ inhibitor. In conclusion, ASPP2 exacerbates ethanol-induced lipid accumulation and hepatic injury by upregulating the PPARγ signaling pathway, thus promoting the occurrence and development of ALD.Graphical

The Protective Role of miR-130b-3p Against Palmitate-Induced Lipotoxicity in Cardiomyocytes Through PPARγ Pathway.

Excess lipid accumulation in the heart is associated with lipotoxicity and cardiac dysfunction due to excessive fatty acid oxidation. Peroxisome proliferator-activated receptor gamma (PPARγ) modulates the expression of key molecules involved in the FA metabolic pathway. Cardiomyocyte-specific overexpression of PPARγ causes dilated cardiomyopathy associated with lipotoxicity in mice. miR-130b-3p has been shown to be downregulated in the plasma of idiopathic dilated cardiomyopathy patients, but its role in modulating cardiomyocyte lipotoxicity via PPARγ remains unclear. Our objective was to investigate the protective role of miR-130b-3p against palmitate-induced lipotoxicity in cardiomyocytes through the modulation of the PPARγ signaling pathway. Human cardiomyoblasts were treated with palmitate. Intracellular lipid accumulation and expression of PPARγ and its downstream targets (CD36, FABP3, CAV1, VLDLR) were analyzed. Mitochondrial oxidative stress was assessed via MitoTracker Green and Redox Sensor Red staining and expression of CPT1B and SOD2. Endoplasmic reticulum stress and apoptosis were determined by examining GRP78, ATF6, XBP1s, CHOP, and caspase-3 expression. miR-130b-3p overexpression was achieved using transfection methods, and its effect on these parameters was evaluated. Luciferase assays were used to confirm PPARγ as a direct target of miR-130b-3p. Palmitate treatment led to increased lipid accumulation and upregulation of PPARγ and its downstream targets in human cardiomyoblasts. Palmitate also increased mitochondrial oxidative stress, endoplasmic reticulum stress and apoptosis. miR-130b-3p overexpression reduced PPARγ expression and its downstream signaling, alleviated mitochondrial oxidative stress and decreased endoplasmic reticulum stress and apoptosis in palmitate-stimulated cardiomyoblasts. Luciferase assays confirmed PPARγ as a direct target of miR-130b-3p. Our findings suggest that miR-130b-3p plays a protective role against palmitate-induced lipotoxicity in cardiomyocytes by modulating the PPARγ signaling pathway.

Kaempferol improves depression-like behaviors through shifting microglia polarization and suppressing NLRP3 via tilting the balance of PPARγ and STAT1 signaling

BackgroundThe pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored. MethodsIn vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein–protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro. ResultsOur results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ antagonist T0070907 or overexpression with CASTAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CASTAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling. ConclusionOur results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.

FGF21 Alleviates Hypoxic-Ischemic White Matter Injury in Neonatal Mice by Mediating Inflammation and Oxidative Stress Through PPAR-γ Signaling Pathway.

White matter injury (WMI), the most common type of brain damage in infants born preterm, is characterized by failure in oligodendrocyte progenitor cell maturation and myelination, thereby contributing to long-term neurological impairments. Regrettably, effective therapies for promoting remyelination and improving function are currently lacking for this growing population affected by WMI. Recombinant human fibroblast growth factor (rhFGF) 21 modulated microglial activation and then ameliorated brain damage and improved neurological deficits in several central nervous system diseases. However, the effects of rhFGF21 treatment on WMI in preterm infants remain uncertain. In this study, we established an in vivo mouse model of cerebral hypoxia-ischemia (HI)-induced brain WMI and an in vitro model using oxygen-glucose deprivation (OGD)-treated HMC3 cells to investigate the neuroprotective effects of rhFGF21 against WMI and elucidated the potential mechanism. Our findings demonstrated that administration of rhFGF21 significantly ameliorated the retardation of oligodendrocyte differentiation, promoted myelination, and mitigated axonal deficits, synaptic loss, and GFAP scarring, thereby improving lifelong cognitive and neurobehavioral dysfunction associated with WMI. Moreover, rhFGF21 modulated microglial polarization, promoted a shift from the M1 to the M2 microglial phenotype, and suppressed microglial activation, thus ameliorating inflammatory response and oxidative stress. Additionally, rhFGF21 treatment significantly inhibited the HMGB1/NF-κB pathway linked to inflammation, and activated the NRF2 pathway associated with oxidative stress through the upregulation of PPAR-γ. Importantly, the beneficial effects of rhFGF21 on HI-induced WMI and microglial activation were dramatically inhibited by PPAR-γ antagonist and its siRNA. Our findings provide compelling evidence that rhFGF21 treatment mitigated the inflammatory response and oxidative stress through the modulation of microglial polarization via the PPAR-γ-mediated HMGB1/NF-κB pathway and the NRF2 pathway, respectively, contributes to neuroprotection and the amelioration of WMI in neonatal mice. Thus, rhFGF21 represents a promising therapeutic agent for the treatment of neonatal WMI.

Cell-state dependent regulation of PPARγ signaling by the transcription factor ZBTB9 in adipocytes

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor that is a master regulator of adipocyte differentiation and function. ZBTB9 is a widely expressed but poorly studied transcription factor that was predicted to interact with PPARγ based on large-scale protein-protein interaction experiments. In addition, genome-wide association studies (GWAS) revealed associations between ZBTB9 and BMI, T2D risk, and HbA1c levels. Here we show that Zbtb9 deficiency in mature adipocytes decreased PPARγ activity and protein level, and thus acts as a positive regulator of PPARγ signaling. In contrast, Zbtb9 deficiency in 3T3-L1 and human preadipocytes increased PPARγ levels and enhanced adipogenesis. Transcriptomic and transcription factor binding site analyses of Zbtb9 deficient preadipocytes revealed that the E2F pathway, controlled by the E2F family of transcription factors that are classically associated with cell cycle regulation, was among the most upregulated pathways. E2F1 positively regulates adipogenesis by promoting Pparg expression, independent of its cell cycle role, via direct binding to the Pparg promoter early during adipogenesis. RB phosphorylation (pRB), which regulates E2F activity, was also upregulated in Zbtb9 deficient preadipocytes. Critically, an E2F1 inhibitor blocked the effects of Zbtb9 deficiency on adipogenesis. Collectively, these results demonstrate that Zbtb9 inhibits adipogenesis as a negative regulator of Pparg expression via pRB-E2F signaling. Our findings reveal cell-state dependent roles of ZBTB9 in adipocytes, identifying a new molecule that regulates adipocyte biology as both a positive and negative regulator of PPARγ signaling depending on the cellular context, and thus may be important in the pathogenesis of obesity and T2D.

Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer's disease.

The profile of autoantibodies is dysregulated in patients with Alzheimer's disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET- CN, 169 Aβ-PET+ cognitively normal subjects (preclinical AD), and 31 Aβ-PET+ cognitively impaired subjects (ClinicalAD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.

LncRNA Snhg3 aggravates hepatic steatosis via PPARγ signaling.

LncRNAs are involved in modulating the individual risk and the severity of progression in metabolic dysfunction-associated fatty liver disease (MASLD), but their precise roles remain largely unknown. This study aimed to investigate the role of lncRNA Snhg3 in the development and progression of MASLD, along with the underlying mechanisms. The result showed that Snhg3 was significantly downregulated in the liver of high-fat diet-induced obesity (DIO) mice. Notably, palmitic acid promoted the expression of Snhg3 and overexpression of Snhg3 increased lipid accumulation in primary hepatocytes. Furthermore, hepatocyte-specific Snhg3 deficiency decreased body and liver weight, alleviated hepatic steatosis and promoted hepatic fatty acid metabolism in DIO mice, whereas overexpression induced the opposite effect. Mechanistically, Snhg3 promoted the expression, stability and nuclear localization of SND1 protein via interacting with SND1, thereby inducing K63-linked ubiquitination modification of SND1. Moreover, Snhg3 decreased the H3K27me3 level and induced SND1-mediated chromatin loose remodeling, thus reducing H3K27me3 enrichment at the Pparg promoter and enhancing PPARγ expression. The administration of PPARγ antagonist T0070907 improved Snhg3-aggravated hepatic steatosis. Our study revealed a new signaling pathway, Snhg3/SND1/H3K27me3/PPARγ, responsible for mice MASLD and indicates that lncRNA-mediated epigenetic modification has a crucial role in the pathology of MASLD.

PPAR-γ Signaling and Common Protective Pathways against Obesity and Alzheimer's Disease

Transcription factor PPAR-γ is predominantly found in adipose tissue, liver, and brain. PPARs form heterodimers, interact with ligands, and regulate the expression of the genes of the PPAR-γ downstream regulatory pathways. PPAR-γ is critical in regulating many physiological processes, including adipogenesis, glucose metabolism, fatty acid metabolism, energy homeostasis, and inflammation. This review is on the functions of PPAR-γ and how dysregulation of activity or expression of PPAR-γ can lead to obesity and Alzheimer's disease (AD). The PPAR- γ agonist inhibited the downregulated pathways, such as Wnt/β-Catenin and JAK-STAT pathways, both involved in activating NF-kB. PPAR-γ has a significant role in the APOE (Apolipoprotein E) gene expression, which reduces reducing obesity, inhibits amyloid aggregation, prevents hyperphosphorylation of tau, and inhibits dysregulation of autophagy. This review provides a perspective on the intricate interplay between PPAR-γ, obesity, and AD, focusing on the molecular mechanisms and potential therapeutic implications.

Rice Protein Peptides Alleviate Alcoholic Liver Disease via the PPARγ Signaling Pathway: Through Liver Metabolomics and Gut Microbiota Analysis.

Alcoholic liver disease (ALD) is the predominant type of liver disease worldwide, resulting in significant mortality and a high disease burden. ALD damages multiple organs, including the liver, gut, and brain, causing inflammation, oxidative stress, and fat deposition. In this study, we investigated the effects of rice protein peptides (RPP) on ALD in mice with a primary focus on the gut microbiota and liver metabolites. The results showed that administration of RPP significantly alleviated the symptoms of ALD in mice including adiposity, oxidative stress, and inflammation. The KEGG pathway shows that RPP downregulates the liver metabolite of capric acid and the metabolism of fatty acid biosynthesis compared with the MOD group. Mechanistically, RPP downregulated the PPARγ signaling pathway and suppressed the expression of fatty acid biosynthesis genes (FASN, ACC1, ACSL1, and ACSL3). Furthermore, two active peptides (YLPTKQ and PKLPR) with potential therapeutic functions for ALD were screened by Caco-2 cell modeling and molecular docking techniques. In addition, RPP treatment alleviates gut microbiota dysbiosis by reversing the F/B ratio, increasing the relative abundance of Alloprevotella and Alistipes, and upregulating the level of short-chain fatty acids. In conclusion, RPP alleviates ALD steatosis through the PPARγ signaling pathway by YLPTKQ and PKLPR and regulates gut microbiota.

Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk.

Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.

Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione's in fructose induced insulin resistant rats

In our pursuit of discovering new antidiabetic agents to manage type 2 diabetes mellitus (T2DM), our approach aimed to identify the bioactive feature/pharmacophore responsible for PPAR-γ expression, as it is accountable for the glucose homeostasis and lipid metabolism. This was achieved by pharmacophore model generation, screening of rationally designed newer thiazolidinedione's library, identifying synthesizing and characterizing the top ten molecules (5a-5j) for their (Invitro &invivo) antidiabetic activity. Preliminary screening of all the ligands by Invitro glucose uptake assay in L6 myotubes (skeletal muscle cell line of rats) revealed compound 5b and 5f stimulated the glucose uptake with 79.29 ± 1.02 % and 74.58 ± 1.02 % respectively compared to pioglitazone with 82.36 ± 0.98 %. This was validated by PPAR-γ TF expression assay, which highlighted a dose dependent increase in transactivation of PPAR-γ. These compounds 5b and 5f were evaluated in fructose induced insulin resistance rat model. Where the treatment with 5b and 5f markedly increased the exogenous clearance of glucose and exogenous insulin via OGTT and ITT respectively, also improved the glucose utilization by significantly increasing content of glycogen and uptake of glucose in rat hemidiaphragm and reversed insulin resistance. Likewise a significant decreased in the VLDL and triglyceride levels was seen in 5b and 5f treated groups compared to insulin resistant (IR) group. It improved glycogenesis by catabolism of glucose and maintained glycaemic control. Similarly it had marked action on enzymatic oxidative biomarkers. Compound 5b displayed better, improved T1/2 (half-life) of 4.21 h and Kel (elimination constant) of 0.381 was noticed in comparison to compound 5f indicating the pharmacokinetic profile. Insilico studies like DFT calculations refined the geometry of 5b and 5f ligands, docking and molecular simulation provided the insights in binding affinity, dynamic behaviour and stability of ligands in PPAR-γ ligand binding domain. MM/GBSA provided the energetics of 5b and 5f in binding pocket. Finally network pharmacology identified ADIPOQ (adiponectin), NR1C3 (PPAR-γ), SLC2A4 (GLUT4), and LEP (leptin) proteins associate with compound 5b and 5f and enriched in Adipocytokine pathway, and PPAR-γ signaling pathway.

Nobiletin Regulates Polyinosinic-polycytidylic Acid-induced Inflammation in Macrophages Partially via the PPAR-γ Signaling Pathway.

Macrophage dysregulation is a common pathogenic feature of viruses that provides extensive targets for antiviral therapy. Nobiletin, a polymethoxylated flavonoid found in citrus fruits, has a multitude of effects. We investigated the effect of nobiletin on polyinosinic-polycytidylic acid (poly(I:C))-induced inflammation in RAW264.7 cells. Nobiletin inhibited the production of poly(I:C)-induced inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and CXCL10. High-throughput sequencing revealed that nobiletin inhibited the expression of TNF-α, IL-6, and CXCL10 and promoted the expression of CD206, Chil3, and Vcam1. In the Kyoto Encyclopedia of Genes and Genomes enrichment analyses, the upregulated differential genes were significantly enriched in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The PPAR-γ inhibitor T0070907 significantly reversed the inhibitory effects of nobiletin on IL-6 and CXCL10 but had no significant effect on TNF-α secretion. Thus, nobiletin regulated poly(I:C)-induced inflammatory responses in RAW264.7 cells partially via the PPAR-γ signaling pathway.

Dual anti-inflammatory effects of curcumin and berberine on acetaminophen-induced liver injury in mice by inhibiting NF-κB activation via PI3K/AKT and PPARγ signaling pathways

Acetaminophen (APAP) overdose is still a leading cause of drug-induced liver injury (DILI), accompanied with severe inflammatory response. However, the therapy for APAP-induced DILI is rather limited. The combined application of natural products to treat DILI induced by APAP may be a new direction of the research. This study was conducted to evaluate the dual anti-inflammatory activity of curcumin (CUR) combined with berberine (BBR) against APAP-mediated DILI. Network pharmacology found that PI3K-Akt and PPAR signaling pathways were primarily involved in anti-DILI of the combination of CUR and BBR. APAP injection enhanced the levels of ALT, AST, IL-1β, IL-6, and TNF-α in mice, while such phenomenon was significantly reversed by the cotreatment of CUR and BBR, which was more effective than either single treatment. The increase of p-NF-κB and p-IKKα/β protein expression and the decrease of p-PI3K, p-AKT, and PPARγ protein expression in APAP-treated mice were markedly inhibited by the coadministration of CUR and BBR. Molecular docking further demonstrated that both CUR and BBR could stably bind to PI3K, AKT, and PPARγ protein. In conclusion, the combination of CUR and BBR more effectively protected liver from APAP-triggered DILI than individual treatment. The mechanism is to alleviate hepatic inflammation by inhibiting NF-κB activation, which is possibly mediated by PI3K/Akt and PPARγ signaling pathways.