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Journal of the American Society of... Apr 2018Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys...
Defects in the renal fatty acid oxidation (FAO) pathway have been implicated in the development of renal fibrosis. Although, compared with young kidneys, aged kidneys show significantly increased fibrosis with impaired kidney function, the mechanisms underlying the effects of aging on renal fibrosis have not been investigated. In this study, we investigated peroxisome proliferator-activated receptor (PPAR) and the FAO pathway as regulators of age-associated renal fibrosis. The expression of PPAR and the FAO pathway-associated proteins significantly decreased with the accumulation of lipids in the renal tubular epithelial region during aging in rats. In particular, decreased PPAR protein expression associated with increased expression of PPAR-targeting microRNAs. Among the microRNAs with increased expression during aging, miR-21 efficiently decreased PPAR expression and impaired FAO when ectopically expressed in renal epithelial cells. In cells pretreated with oleic acid to induce lipid stress, miR-21 treatment further enhanced lipid accumulation. Furthermore, treatment with miR-21 significantly exacerbated the TGF--induced fibroblast phenotype of epithelial cells. We verified the physiologic importance of our findings in a calorie restriction model. Calorie restriction rescued the impaired FAO pathway during aging and slowed fibrosis development. Finally, compared with kidneys of aged littermate controls, kidneys of aged PPAR mice showed exaggerated lipid accumulation, with decreased activity of the FAO pathway and a severe fibrosis phenotype. Our results suggest that impaired renal PPAR signaling during aging aggravates renal fibrosis development, and targeting PPAR is useful for preventing age-associated CKD.
Topics: Aging; Animals; Caloric Restriction; Cell Line; Epithelial Cells; Extracellular Matrix Proteins; Fatty Acids; Fibrosis; Gene Expression Regulation; Kidney; Mice; Mice, Knockout; MicroRNAs; Oleic Acid; Oxidation-Reduction; PPAR alpha; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta
PubMed: 29440279
DOI: 10.1681/ASN.2017070802 -
British Journal of Pharmacology Nov 2018Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the...
BACKGROUND AND PURPOSE
Nuciferine, an alkaloid found in Nelumbo nucifera leaves, alleviates dyslipidemia in vivo. However, whether it improves liver injury in diabetic conditions and the underlying mechanism is unclear. The present study aimed to investigate the effects of nuciferine on lipid and glucose metabolism in a murine model of Type 2 diabetes mellitus (T2DM) and to determine the underlying mechanisms of these effects.
EXPERIMENTAL APPROACH
A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with nuciferine in their food. The underlying mechanism of the anti-steatotic effect of nuciferine was further explored in HepG2 hepatocytes cultured with palmitic acid. Major signalling profiles involved in fatty acid oxidation were then evaluated, using Western blot, RT-qPCR and si-RNA techniques, along with immunohistochemistry.
KEY RESULTS
Nuciferine restored impaired glucose tolerance and insulin resistance in diabetic mice. Hepatic levels of total cholesterol, triglycerides and LDL were decreased, as were the number of lipid droplets, by nuciferine treatment. Furthermore, nuciferine up-regulated β-oxidation related genes in livers of diabetic mice. Luciferase reporter cell assay showed that nuciferine directly reversed palmitic acid-induced inhibition of PPARα transcriptional activity. Silencing PPARγ coactivator-1α (PGC1α) expression in HepG2 cells abolished the effects of nuciferine in accelerating β-oxidation.
CONCLUSIONS AND IMPLICATIONS
Nuciferine improved lipid profile and attenuated hepatic steatosis in HFD/STZ-induced diabetic mice by activating the PPARα/PGC1α pathway. Nuciferine may be a potentially important candidate in improving hepatic steatosis and the management of T2DM.
Topics: Animals; Aporphines; Diabetes Mellitus, Experimental; Diet, High-Fat; Fatty Liver; Glucose Tolerance Test; Hep G2 Cells; Humans; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; PPAR alpha; Streptozocin; Transcription Factors
PubMed: 30129056
DOI: 10.1111/bph.14482 -
Nature Cell Biology Nov 2022Tumour cells exhibit greater metabolic plasticity than normal cells and possess selective advantages for survival and proliferation with unclearly defined mechanisms....
Tumour cells exhibit greater metabolic plasticity than normal cells and possess selective advantages for survival and proliferation with unclearly defined mechanisms. Here we demonstrate that glucose deprivation in normal hepatocytes induces PERK-mediated fructose-1,6-bisphosphatase 1 (FBP1) S170 phosphorylation, which converts the FBP1 tetramer to monomers and exposes its nuclear localization signal for nuclear translocation. Importantly, nuclear FBP1 binds PPARα and functions as a protein phosphatase that dephosphorylates histone H3T11 and suppresses PPARα-mediated β-oxidation gene expression. In contrast, FBP1 S124 is O-GlcNAcylated by overexpressed O-linked N-acetylglucosamine transferase in hepatocellular carcinoma cells, leading to inhibition of FBP1 S170 phosphorylation and enhancement of β-oxidation for tumour growth. In addition, FBP1 S170 phosphorylation inversely correlates with β-oxidation gene expression in hepatocellular carcinoma specimens and patient survival duration. These findings highlight the differential role of FBP1 in gene regulation in normal and tumour cells through direct chromatin modulation and underscore the inactivation of its protein phosphatase function in tumour growth.
Topics: Humans; Carcinoma, Hepatocellular; Histones; Fructose-Bisphosphatase; PPAR alpha; Fructose; Liver Neoplasms; Transcription, Genetic; Phosphoprotein Phosphatases
PubMed: 36266488
DOI: 10.1038/s41556-022-01009-4 -
Biochemical Pharmacology Feb 2023Vascular calcification, a prevalent pathological alteration in metabolic syndromes, is tightly related with cardiometabolic risk events. Ferroptosis, a newly...
Oleoylethanolamide alleviates hyperlipidaemia-mediated vascular calcification via attenuating mitochondrial DNA stress triggered autophagy-dependent ferroptosis by activating PPARα.
Vascular calcification, a prevalent pathological alteration in metabolic syndromes, is tightly related with cardiometabolic risk events. Ferroptosis, a newly iron-dependent programmed cell death, induced by palmitic acid (PA), the major saturated free fatty acid in hyperlipidemia, is a vital mechanism of vascular calcification. Recent studies reported that ferroptosis is a distinctive type of cell death dependent on autophagy, with the lipotoxicity of PA on cell viability being closely linked with autophagy. Oleoylethanolamide (OEA), an endogenous bioactive mediator of lipid homeostasis, exerts vascular protection against intimal calcification, atherosclerosis; however, its beneficial effect on vascular smooth muscle cell (VSMC)-associated medial calcification has not been investigated. Our aim was to characterize the effect of OEA on vascular calcification and ferroptosis of VSMCs under hyperlipidaemia/PA exposure. In vivo, vascular calcification model was induced in rats by high-fat diet and vitamin D3 plus nicotine; in vitro, VSMCs ferroptosis was induced by PA or plus β-glycerophosphate mimicking vascular calcification. The calcium deposition in hyperlipidaemia-mediated rat thoracic aortas, the PA-induced ferroptosis and subsequent calcium deposition in VSMCs, were suppressed by OEA treatment. Additionally, CGAS-STING1-induced ferritinophagy, the main molecular mechanism of PA-triggered ferroptosis of VSMCs, was activated by mitochondrial DNA damage; however, early administration of OEA alleviated these phenomena. Intriguingly, overexpression of peroxisome proliferator activated receptor alpha (PPARα) contributed to a decrease in PA-induced ferroptosis, whereas PPARɑ knockdown inhibited the OEA-mediated anti-ferroptotic effects. Collectively, our study demonstrated that OEA serves as a prospective candidate for the prevention and treatment of vascular calcification in metabolic abnormality syndromes.
Topics: Rats; Animals; PPAR alpha; DNA, Mitochondrial; Ferroptosis; Calcium; Hyperlipidemias; Vascular Calcification; Fatty Acids; Palmitic Acid; Autophagy; Myocytes, Smooth Muscle
PubMed: 36525991
DOI: 10.1016/j.bcp.2022.115379 -
Current Alzheimer Research Feb 2018The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called "amyloid cascade hypothesis" has long been the prevailing... (Review)
Review
BACKGROUND
The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called "amyloid cascade hypothesis" has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD.
CONCLUSION
This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.
Topics: Alzheimer Disease; Animals; Antipsychotic Agents; Central Nervous System; Humans; PPAR alpha
PubMed: 28474570
DOI: 10.2174/1567205014666170505094549 -
Biological Psychiatry Oct 2023The gut microbiome regulates emotional behavior, stress responses, and inflammatory processes by communicating with the brain. How and which neurobiological mediators... (Review)
Review
The gut microbiome regulates emotional behavior, stress responses, and inflammatory processes by communicating with the brain. How and which neurobiological mediators underlie this communication remain poorly understood. PPAR-α (peroxisome proliferator-activated receptor α), a transcription factor susceptible to epigenetic modifications, regulates pathophysiological functions, including metabolic syndrome, inflammation, and behavior. Mood disorders, inflammatory processes, and obesity are intertwined phenomena that are associated with low blood concentrations of the anti-inflammatory and "endogenous tranquilizer" neurosteroid allopregnanolone and poor PPAR-α function. Stress and consumption of obesogenic diets repress PPAR function in brain, enterocytes, lipocytes, and immune modulatory cells favoring inflammation, lipogenesis, and mood instability. Conversely, micronutrients and modulators of PPAR-α function improve microbiome composition, dampen systemic inflammation and lipogenesis, and improve anxiety and depression. In rodent stress models of anxiety and depression, PPAR activation normalizes both PPAR-α expression downregulation and decreased allopregnanolone content and ameliorates depressive-like behavior and fear responses. PPAR-α is known to regulate metabolic and inflammatory processes activated by short-chain fatty acids; endocannabinoids and congeners, such as N-palmitoylethanolamide, drugs that treat dyslipidemias; and micronutrients, including polyunsaturated fatty acids. Both PPAR-α and allopregnanolone are abundantly expressed in the colon, and they exert potent anti-inflammatory actions by blocking the toll-like receptor-4-nuclear factor-κB pathway in peripheral immune cells, neurons, and glia. The perspective that PPAR-α regulation in the colon by gut microbiota or metabolites influences central allopregnanolone content after trafficking to the brain, thereby serving as a mediator of gut-brain axis communications, is examined in this review.
Topics: Humans; Pregnanolone; Brain-Gut Axis; Brain; PPAR alpha; Inflammation
PubMed: 37156350
DOI: 10.1016/j.biopsych.2023.04.025 -
Drugs Oct 2017Pemafibrate (Parmodia) is a novel, highly selective peroxisome proliferator-activated receptor (PPAR)-α modulator (SPPARM). It acts by binding to PPAR-α and regulating... (Review)
Review
Pemafibrate (Parmodia) is a novel, highly selective peroxisome proliferator-activated receptor (PPAR)-α modulator (SPPARM). It acts by binding to PPAR-α and regulating the expression of target genes that modulate lipid metabolism, thereby decreasing plasma triglyceride levels and increasing high-density lipoprotein cholesterol levels. Developed by Kowa Company, Ltd., oral pemafibrate has been approved in Japan for the treatment of hyperlipidaemia (including familial hyperlipidaemia). This article summarizes the milestones in the development of pemafibrate leading to this first global approval for hyperlipidaemia.
Topics: Benzoxazoles; Butyrates; Cholesterol, HDL; Drug Approval; Humans; Hyperlipidemias; Lipid Metabolism; Lipoproteins, HDL; PPAR alpha; Protein Binding
PubMed: 28929345
DOI: 10.1007/s40265-017-0818-x -
Biomolecules & Biomedicine May 2023Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic... (Review)
Review
Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.
Topics: Humans; Fenofibrate; PPAR alpha; Anti-Inflammatory Agents; Inflammation; Hyperlipidemias; Lipids
PubMed: 36724021
DOI: 10.17305/bb.2022.8534 -
Journal of Ethnopharmacology May 2024Nonalcoholic steatohepatitis (NASH) is a prominent cause of liver-related death that poses a threat to global health and is characterized by severe hepatic steatosis,...
BACKGROUND
Nonalcoholic steatohepatitis (NASH) is a prominent cause of liver-related death that poses a threat to global health and is characterized by severe hepatic steatosis, lobular inflammation, and ballooning degeneration. To date, no Food and Drug Administration-approved medicine is commercially available. The Chaihu Guizhi Ganjiang Decoction (CGGD) shows potential curative effects on regulation of blood lipids and blood glucose, mitigation of organism inflammation, and amelioration of hepatic function. However, the overall regulatory mechanisms underlying its effects on NASH remain unclear.
PURPOSE
This study aimed to investigate the efficiency of CGGD on methionine- and choline-deficient (MCD)-induced NASH and unravel its underlying mechanisms.
METHODS
A NASH model of SD rats was established using an MCD diet for 8 weeks, and the efficacy of CGGD was evaluated based on hepatic lipid accumulation, inflammatory response, and fibrosis. The effects of CGGD on the intestinal barrier, metabolic profile, and differentially expressed genes (DEGs) profile were analyzed by integrating gut microbiota, metabolomics, and transcriptome sequencing to elucidate its mechanisms of action.
RESULTS
In MCD-induced NASH rats, pathological staining demonstrated that CGGD alleviated lipid accumulation, inflammatory cell infiltration, and fibrosis in the hepatic tissue. After CGGD administration, liver index, liver weight, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) contents, liver triglycerides (TG), and free fatty acids (FFAs) were decreased, meanwhile, it down-regulated the level of proinflammatory mediators (TNF-α, IL-6, IL-1β, MCP-1), and up-regulated the level of anti-inflammatory factors (IL-4, IL-10), and the expression of liver fibrosis markers TGFβ, Acta2, Col1a1 and Col1a2 were weakened. Mechanistically, CGGD treatment altered the diversity of intestinal flora, as evidenced by the depletion of Allobaculum, Blautia, norank_f_Erysipelotrichaceae, and enrichment of the probiotic genera Roseburia, Lactobacillus, Lachnoclostridium, etc. The colonic histopathological results indicated that the gut barrier damage recovered in the CGGD treatment group, and the expression levels of colonic short-chain fatty acids (SCFAs)-specific receptors FFAR2, FFAR3, and tight junction (TJs) proteins ZO-1, Occludin, Claudin-1 were increased compared with those in the model group. Further metabolomic and transcriptomic analyses suggested that CGGD mitigated the lipotoxicity caused by glycerophospholipid and eicosanoid metabolism disorders by decreasing the levels of PLA2G4A, LPCAT1, COX2, and LOX5. In addition, CGGD could activate the inhibitory lipotoxic transcription factor PPARα, regulate the proteins of FABP1, APOC2, APOA2, and LPL to promote fatty acid catabolism, and suppress the TLR4/MyD88/NFκB pathway to attenuate NASH.
CONCLUSION
Our study demonstrated that CGGD improved steatosis, inflammation, and fibrosis on NASH through enhancing intestinal barrier integrity and alleviating PPARα mediated lipotoxicity, which makes it an attractive candidate for potential new strategies for NASH prevention and treatment.
Topics: Rats; Animals; Mice; Non-alcoholic Fatty Liver Disease; PPAR alpha; Rats, Sprague-Dawley; Liver; Liver Cirrhosis; Inflammation; Lipids; Methionine; Mice, Inbred C57BL; Drugs, Chinese Herbal
PubMed: 38310988
DOI: 10.1016/j.jep.2024.117841 -
Frontiers in Endocrinology 2022Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is involved in lipid metabolism of various tissues. Different... (Review)
Review
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is involved in lipid metabolism of various tissues. Different metabolites of fatty acids and agonists like fibrates activate PPARα for its transactivative or repressive function. PPARα is known to affect diverse human diseases, and we focus on advanced studies of its transcriptional regulation in these diseases. In MAFLD, PPARα shows a protective function with its upregulation of lipid oxidation and mitochondrial biogenesis and transcriptional repression of inflammatory genes, which is similar in Alzheimer's disease and cardiovascular disease. Activation of PPARα also prevents the progress of diabetes complications; however, its role in diabetes and cancers remains uncertain. Some PPARα-specific agonists, such as Wy14643 and fenofibrate, have been applied in metabolic syndrome treatment, which might own potential in wider application. Future studies may further explore the functions and interventions of PPARα in cancer, diabetes, immunological diseases, and neurodegenerative disease.
Topics: Humans; Cardiovascular Diseases; Fenofibrate; Metabolic Syndrome; Neurodegenerative Diseases; PPAR alpha
PubMed: 36589809
DOI: 10.3389/fendo.2022.1074911