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Free Radical Biology & Medicine Nov 2023Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα)...
Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.
Topics: Humans; Podocytes; PPAR alpha; Diabetic Nephropathies; Ubiquitin-Protein Ligases; Proteinuria; Doxorubicin; Renal Insufficiency, Chronic; Fatty Acids
PubMed: 37793501
DOI: 10.1016/j.freeradbiomed.2023.09.039 -
Journal of Ethnopharmacology Jul 2023Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula chronicled in Shang Han Lun, is safe and effective for treatment of ulcerative colitis (UC).
ETHNOPHARMACOLOGICAL RELEVANCE
Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula chronicled in Shang Han Lun, is safe and effective for treatment of ulcerative colitis (UC).
AIM OF THE STUDY
To investigate the effect of HQD against dextran sulfate sodium (DSS)-induced UC mice by regulating gut microbiota and metabolites, and further explore the mechanism of fatty acid metabolism on macrophage polarization.
MATERIALS AND METHODS
Based on 3% dextran sulfate sodium (DSS)-induced UC mice model, clinical symptoms observation (body weight, DAI, and colon length) and histological inspection were used to evaluate the efficacy of HQD and fecal microbiota transplantation (FMT) from HQD-treated mice. The gut microbiota and metabolites were detected by 16S rRNA sequencing and metabolomics analysis. The parameters of fatty acid metabolism, macrophage polarization, and FFAR1/FFAR4-AMPK-PPARα pathway were analyzed by immunofluorescence analysis, western blotting, and real-time PCR. Then, the effects of FFAR1 and FFAR4 on macrophage polarization were examined by agonists based on LPS-induced RAW264.7 cell model.
RESULTS
The results showed that FMT, like HQD, ameliorated UC by improving weight loss, restoring colon length, and reducing DAI scores and histopathological scores. Besides, HQD and FMT both enhanced the richness of gut microbiota, and modulated intestinal bacteria and metabolites to achieve a new balance. Untargeted metabolomics analysis revealed that fatty acids, especially long-chain fatty acids (LCFAs), dominated in HQD against DSS-induced UC by regulating the gut microenvironment. Further, FMT and HQD recovered the expression of fatty acid metabolism-related enzymes, and simultaneously activated FFAR1/FFAR4-AMPK-PPARα pathway but suppressed NF-κB pathway. Combined with cell experiment, HQD and FMT promoted macrophage polarization from M1 toward M2, which were well associated with anti-inflammatory cytokines and combined with the activated FFAR4.
CONCLUSIONS
The mechanism of HQD against UC was related to regulating fatty acid metabolism to mediate M2 macrophage polarization by activating the FFAR4-AMPK-PPARα pathway.
Topics: Animals; Mice; PPAR alpha; AMP-Activated Protein Kinases; Scutellaria baicalensis; Colitis, Ulcerative; Dextran Sulfate; RNA, Ribosomal, 16S; Colon; Disease Models, Animal; Fatty Acids; Colitis; Mice, Inbred C57BL
PubMed: 36997133
DOI: 10.1016/j.jep.2023.116430 -
Frontiers in Pharmacology 2023Aluminium (Al) is accumulated in the brain causing neurotoxicity and neurodegenerative disease like Alzheimer's disease (AD), multiple sclerosis, autism and epilepsy....
The protective effects of sesamol and/or the probiotic, , against aluminum chloride-induced neurotoxicity and hepatotoxicity in rats: Modulation of Wnt/β-catenin/GSK-3β, JAK-2/STAT-3, PPAR-γ, inflammatory, and apoptotic pathways.
Aluminium (Al) is accumulated in the brain causing neurotoxicity and neurodegenerative disease like Alzheimer's disease (AD), multiple sclerosis, autism and epilepsy. Hence, attenuation of Al-induced neurotoxicity has become a "hot topic" in looking for an intervention that slow down the progression of neurodegenerative diseases. Our study aims to introduce a new strategy for hampering aluminum chloride (AlCl3)-induced neurotoxicity using a combination of sesamol with the probiotic bacteria; and also to test their possible ameliorative effects on AlCl-induced hepatotoxicity. Sprague-Dawley male rats were randomly divided into five groups (n = 10/group) which are control, AlCl, AlCl + Sesamol, AlCl + and AlCl + Sesamol + . We surveilled the behavioral, biochemical, and histopathological alterations centrally in the brain and peripherally in liver. This work revealed that the combined therapy of sesamol and produced marked reduction in brain amyloid-β, p-tau, GSK-3β, inflammatory and apoptotic biomarkers, along with marked elevation in brain free β-catenin and Wnt3a, compared to AlCl-intoxicated rats. Also, the combined therapy exerted pronounced reduction in hepatic expressions of JAK-2/STAT-3, inflammatory (TNF-α, IL-6, NF-κB), fibrotic (MMP-2, TIMP-1, α-SMA) and apoptotic markers, (caspase-3), together with marked elevation in hepatic PPAR-γ expression, compared to AlCl -intoxicated rats. Behavioral and histopathological assessments substantiated the efficiency of this combined regimen in halting the effect of neurotoxicity. Probiotics can be used as an add-on therapy with sesamol ameliorate AlCl -mediated neurotoxicity and hepatotoxicity.
PubMed: 37601053
DOI: 10.3389/fphar.2023.1208252 -
Hepatology (Baltimore, Md.) Jul 2024
Topics: PPAR alpha; Humans; PPAR delta; Animals; Mice; Fatty Liver
PubMed: 38373084
DOI: 10.1097/HEP.0000000000000791 -
Journal of Ethnopharmacology May 2024Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be...
Anchang Yuyang Decoction inhibits experimental colitis-related carcinogenesis by regulating PPAR signaling pathway and affecting metabolic homeostasis of host and microbiota.
ETHNOPHARMACOLOGICAL RELEVANCE
Inflammatory bowel disease (IBD) presents a risk of carcinogenesis, which escalates with the duration of IBD. Persistent histological inflammation is considered to be the driving factor of colitis carcinogenesis. Effective control of inflammation is helpful to prevent and treat colitis-related colorectal cancer (CAC). Anchang Yuyang Decoction (AYD), a traditional Chinese medicine (TCM) formula, is originated from the ancient prescription of TCM for treating colitis and colorectal cancer. AYD has demonstrated efficacy in treating IBD and potential anti-carcinogenic properties.
AIM OF THE STUDY
This research aims to assess the therapeutic efficacy of AYD in ameliorating experimental colitis-related carcinogenesis induced by AOM/DSS. It further seeks to elucidate its potential mechanisms by integrating multiple omics sequencing approaches.
MATERIALS AND METHODS
A rat model for colitis-related carcinogenesis was developed using azoxymethane (AOM)/dextran sulfate sodium (DSS). UPLC-MS identified AYD's chemical constituents. Rats were administered varying doses of AYD (18.37, 9.19 and 4.59 g/kg) orally for 53 days, with mesalazine as a positive control. The study evaluated anti-carcinogenic effects by examining adenoma number, adenoma load, abnormal crypt foci (ACF), histopathological damage, and tumor-related protein expression. Anti-inflammatory and reparative effects were assessed through body weight, disease activity index (DAI), colon length, spleen index, inflammatory cytokine levels, and tight junction protein expression. The effects on intestinal microbiota and host metabolism were explored through 16S rRNA sequencing, targeted short-chain fatty acid (SCFA) metabonomics, and non-targeted colon metabolomics. Potential AYD targets were identified through transcriptomic sequencing and validated by qRT-PCR and western blotting.
RESULTS
AYD significantly reduced adenoma number, adenoma load, neoplasm-associated lesions, ACF, and tumor-related protein expression (e.g., p53, PCNA) in AOM/DSS-induced rats, thus impeding colitis-related carcinogenesis progression. AYD also alleviated histopathological damage and inflammation, promoting intestinal mucosal barrier repair. Furthermore, AYD modulated intestinal flora structure, enhanced SCFA production, and regulated colon metabolites. Transcriptomic sequencing revealed a significant impact on the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Subsequent qRT-PCR and western blotting experiments indicated AYD's influence in up-regulating PPAR-γ and down-regulating PPAR-α, PPAR-β/δ, and related proteins (thrombomodulin [Thbd], fatty acid binding protein 5 [Fabp5], stearoyl-CoA desaturase 2 [Scd2], phospholipid transfer protein [Pltp]).
CONCLUSIONS
This study demonstrates AYD's ability to inhibit experimental colitis-related carcinogenesis induced by AOM/DSS. Its mechanism likely involves modulation of the PPAR signaling pathway, impacting intestinal microbiota and host metabolic equilibrium.
Topics: Rats; Animals; Mice; Peroxisome Proliferator-Activated Receptors; RNA, Ribosomal, 16S; Chromatography, Liquid; Tandem Mass Spectrometry; Colitis; Inflammation; Signal Transduction; Inflammatory Bowel Diseases; Carcinogenesis; Azoxymethane; Gastrointestinal Microbiome; Colorectal Neoplasms; Homeostasis; Adenoma; Dextran Sulfate; Disease Models, Animal; Mice, Inbred C57BL; Colon
PubMed: 38428656
DOI: 10.1016/j.jep.2024.117995 -
Molecular Psychiatry Oct 2023Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ-tetrahydrocannabinol (Δ-THC) is a PPARγ agonist...
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ-tetrahydrocannabinol (Δ-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60% of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ-THC-induced reduction in oICSS and Δ-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ-THC-induced hypoactivity and catalepsy but failed to alter Δ-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.
Topics: Mice; Animals; PPAR alpha; Dopamine; Cannabinoids; PPAR gamma; Dronabinol; Dopaminergic Neurons; Mesencephalon
PubMed: 37479780
DOI: 10.1038/s41380-023-02182-0 -
Nature Communications Nov 2023Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left...
Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics and pharmacological intervention showed that FBXW7 loss-of-function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression in male mice. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH.
Topics: Animals; Male; Mice; F-Box-WD Repeat-Containing Protein 7; Hepatocytes; Homeostasis; Liver; Liver Neoplasms; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Nutrients; PPAR alpha; Receptors, Cytoplasmic and Nuclear
PubMed: 37914694
DOI: 10.1038/s41467-023-42785-3 -
Poultry Science Feb 2024Fatty liver hemorrhage syndrome (FLHS) is the leading cause of noninfectious mortality in caged layers worldwide. Osteocalcin (OCN) is a protein secreted by osteoblasts,...
Fatty liver hemorrhage syndrome (FLHS) is the leading cause of noninfectious mortality in caged layers worldwide. Osteocalcin (OCN) is a protein secreted by osteoblasts, and its undercarboxylated form (ucOCN) acts as a multifunctional hormone that protects laying hens from FLHS. Lipophagy is a form of selective autophagy that breaks down lipid droplets (LDs) through lysosomes, and defective lipophagy is associated with FLHS. The aim of this study was to investigate the effects of ucOCN on the lipophagy of chicken embryonic hepatocytes and associated the function of the adiponectin (ADPN) signaling pathway. In this study, chicken embryonic hepatocytes were divided into 5 groups: control (CONT), fat emulsion (FE, 10% FE, v/v), FE with ucOCN at 1 ng/mL (FE-LOCN), 3 ng/mL (FE-MOCN), and 9 ng/mL (FE-HOCN). In addition, 4 μM AdipoRon, an adiponectin receptor agonist, was used to investigate the function of ADPN. The results showed that compared with CONT group, FE promoted the levels of phosphorylation of mammalian target of rapamycin (p-mTOR) (P < 0.05) and decreased the mRNA expression of ADNP receptors (AdipoR1 and AdipoR2). Compared with FE group, 3 and 9 ng/mL ucOCN inhibited the levels of autophagy adaptor p62 and p-mTOR (P < 0.05), increased the ratios of LC3-II/LC3-I (P < 0.05) and phosphorylated adenosine 5'-monophosphate-activated protein kinase (p-AMPK)/AMPK (P < 0.05), as well as the levels of peroxisome proliferator-activated receptor α (PPAR-α) and ADPN (P < 0.05). In addition, ucOCN at the tested concentrations increased the colocalization of LC3 and LDs in fatty hepatocytes. Administrated 4 μM AdipoRon activated AdipoR1 and AidpoR2 mRNA expression (P < 0.05), decreased the concentrations of triglyceride (P < 0.05), without effects on cell viability (P > 0.05). AdipoRon also increased the LC3-II/LC3-I ratio (P < 0.05) and the levels of p-AMPK/AMPK and PPAR-α (P < 0.05). In conclusion, the results reveal that ucOCN regulates lipid metabolism by activating lipophagy via the ADPN-AMPK/PPARα-mTOR signaling pathway in chicken embryonic hepatocytes. The results may provide new insights for controlling FLHS in laying hens.
Topics: Chick Embryo; Animals; Female; PPAR alpha; Chickens; AMP-Activated Protein Kinases; Adiponectin; Osteocalcin; Hepatocytes; Signal Transduction; TOR Serine-Threonine Kinases; Hemorrhage; Autophagy; RNA, Messenger; Mammals; Abnormalities, Multiple; Growth Disorders; Heart Septal Defects, Ventricular; Craniofacial Abnormalities
PubMed: 38070403
DOI: 10.1016/j.psj.2023.103293 -
Molecules (Basel, Switzerland) Dec 2023Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for...
Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (, , , ) were designed and synthesized. The target product (compound ) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 μM of compound reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.
Topics: Humans; Lipid Metabolism; PPAR alpha; Carnitine O-Palmitoyltransferase; Non-alcoholic Fatty Liver Disease; Antipsychotic Agents; Ethylamines; Oleic Acid; Lipase; Indoles
PubMed: 38202597
DOI: 10.3390/molecules29010012 -
Cureus Aug 2023Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease (NAFLD), which, apart from excess fat in the liver, may be characterised by some... (Review)
Review
Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease (NAFLD), which, apart from excess fat in the liver, may be characterised by some level of inflammatory infiltration and fibrogenesis, occasionally progressing to liver cirrhosis or hepatocellular carcinoma (HCC). The objective of the current review is to elucidate the rising prevalence, the role of microbiome and genetics in pathogenesis, diagnostic challenges, and novel treatment alternatives for NASH. Newer diagnostic techniques are being developed since using liver biopsy in a larger population is not a reasonable option and is primarily restricted to clinical research, at least in developing countries. Besides these technical challenges, another important factor leading to deviation from guideline practice is the lack of health insurance coverage in countries like India. It leads to reluctance on the part of physicians and patients to delay required tests to curb out-of-pocket expenditure. There is no cure for NASH, with liver transplantation remaining the last option for those who progress to end-stage liver disease (ESLD) or are detected with early-stage HCC. Thus, lifestyle modification remains the only viable option for many, but compliance and long-term adherence remain major challenges. In obese individuals, bariatric surgery and weight reduction have shown favourable results. In patients with less severe obesity, endoscopic bariatric metabolic therapies (EBMT) are rapidly emerging as less invasive therapies. However, access and acceptability remain poor for these weight reduction methods. Therefore, intense research is being conducted for potential newer drug classes with several agents currently in phase II or III of clinical development. Some of these have demonstrated promising results, such as a reduction in hepatic fat content, and attenuation of fibrosis with an acceptable tolerability profile in phase II studies. The developments in the management of NASH have been fairly encouraging. Further well-designed long-term prospective studies should be undertaken to generate evidence with definitive results.
PubMed: 37664266
DOI: 10.7759/cureus.42852