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Planta Medica May 2022Quercetin, a flavonol, is a functional compound that is abundant in onions and is known to have antioxidant and anti-inflammatory effects. Quercetin and its glucoside...
Quercetin, a flavonol, is a functional compound that is abundant in onions and is known to have antioxidant and anti-inflammatory effects. Quercetin and its glucoside are known to function as peroxisome proliferator-activated receptor (PPAR) ligands and showed high PPAR- transactivation activity but little PPAR- transactivation activity in some reports. In this study, we demonstrated that an aqueous extract of a quercetin-rich onion cultivar increased transactivation activities not only of PPAR- but also of PPAR-. We isolated (9,12,13)-(10)-9,12,13-trihydroxyoctadec-10-enoic acid (pinellic acid) obtained from the aqueous extract using PPAR- transactivation as an index. Furthermore, it was revealed that pinellic acid could transactivate PPAR-. Our findings are the first report mentioned showing that trihydroxyoctadec-10-enoic acids showed PPAR-/ transactivation activities.
Topics: Fatty Acids, Unsaturated; Onions; PPAR alpha; PPAR gamma; Quercetin; Transcriptional Activation
PubMed: 35038752
DOI: 10.1055/a-1345-9471 -
Reviews in Endocrine & Metabolic... Oct 2022Both nuclear receptors glucocorticoid receptor α (GRα) and peroxisome proliferator-activated receptor α (PPARα) are involved in energy and lipid metabolism, and... (Review)
Review
Both nuclear receptors glucocorticoid receptor α (GRα) and peroxisome proliferator-activated receptor α (PPARα) are involved in energy and lipid metabolism, and possess anti-inflammation effects. Previous studies indicate that a regulatory loop may exist between them. In vivo and in vitro studies showed that glucocorticoids stimulate hepatic PPARα expression via GRα at the transcriptional level. This stimulation of PPARα by GRα has physiological relevance and PPARα is involved in many glucocorticoid-induced pathophysiological processes, including gluconeogenesis and ketogenesis during fasting, insulin resistance, hypertension and anti-inflammatory effects. PPARα also synergizes with GRα to promote erythroid progenitor self-renewal. As the feedback, PPARα inhibits glucocorticoid actions at pre-receptor and receptor levels. PPARα decreases glucocorticoid production through inhibiting the expression and activity of type-1 11β-hydroxysteroid dehydrogenase, which converts inactive glucocorticoids to active glucocorticoids at local tissues, and also down-regulates hepatic GRα expression, thus forming a complete and negative feedback loop. This negative feedback loop sheds light on prospective multi-drug therapeutic treatments in inflammatory diseases through a combination of glucocorticoids and PPARα agonists. This combination may potentially enhance the anti-inflammatory effects while alleviating side effects on glucose and lipid metabolism due to GRα activation. More investigations are needed to clarify the underlying mechanism and the relevant physiological or pathological significance of this regulatory loop.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Anti-Inflammatory Agents; Feedback; Glucocorticoids; Glucose; Humans; PPAR alpha; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Glucocorticoid
PubMed: 35476174
DOI: 10.1007/s11154-022-09725-w -
Cellular and Molecular Gastroenterology... 2022The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no...
BACKGROUND & AIMS
The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.
METHODS
The clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.
RESULTS
Serum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.
CONCLUSIONS
Liver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.
Topics: Animals; Mice; Antibodies, Neutralizing; Choline; Diet, High-Fat; Hepatocytes; Lysophosphatidylcholines; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; PPAR alpha; Phosphoric Diester Hydrolases
PubMed: 35931383
DOI: 10.1016/j.jcmgh.2022.07.012 -
International Journal of Cancer Apr 2023The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that...
The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH ) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH , but not at acidic pH . Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.
Topics: Humans; Transcription Factors; Gene Expression Regulation; PPAR alpha; Fatty Acids; Neoplasms; Acidosis; Lipid Metabolism; Liver; Tumor Microenvironment
PubMed: 36533672
DOI: 10.1002/ijc.34404 -
Prostaglandins & Other Lipid Mediators Dec 2022The high-fat diet (HFD) promotes obesity and develops inflammation, causing dysregulation of energy metabolism and prostatic neoplastic tissue changes. PPARɑ deletion...
The high-fat diet (HFD) promotes obesity and develops inflammation, causing dysregulation of energy metabolism and prostatic neoplastic tissue changes. PPARɑ deletion leads to loss of homeostasis between the pro and anti-inflammatory response, and dysregulation of lipid metabolism, causing changes in different physiological processes and damage to the prostate. On the other hand, aerobic physical exercise has been suggested as a non-pharmacological tool to improve energy metabolism and cellular metabolism in the prostate, however, the underlying molecular mechanism remains unclear. the current study aimed to evaluate PPARα as a possible regulator of the protective effects of aerobic physical exercise in the prostate by examining prostatic alterations in wild-type and PPARα deletion mice fed a standard diet or an HFD. Wild-type and PPARα-null mice were fed a standard or HFD diet for 12 weeks, and submitted to aerobic physical exercise for 8 weeks. The HFD promoted the increase of inflammatory markers IL-6, TNF-α, NF-kB, and an increase of inflammatory foci in animals in both genotypes. Although the PPARα deletion animals submitted to the aerobic physical exercise were not able to regulate response pro-inflammatory, but promoted an increase in IL-10 in the prostate. In animals WT, the aerobic physical exercise, reduced all inflammatory markers, improve the inflammatory response, and showed a higher expression of BAX and IL-10 proteins was protective against prostatic tissue lesions. Suggested that PPARα deletion associated with HFD suppressed apoptosis and increased damage prostate. On other hand, aerobic physical exercise improves prostatic tissue by increasing the response to anti-inflammatory and apoptosis protein.
Topics: Animals; Male; Mice; Apoptosis; Diet, High-Fat; Interleukin-10; Mice, Inbred C57BL; Mice, Knockout; PPAR alpha; Physical Conditioning, Animal; Prostate
PubMed: 35963510
DOI: 10.1016/j.prostaglandins.2022.106669 -
Clinical Science (London, England :... Jan 2021Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin....
Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.
Topics: Angiotensin II; Animals; Apoptosis; Fibrosis; Gastrins; Humans; Hypertension; Hypertension, Renal; Jurkat Cells; Kidney Tubules, Proximal; Mice; Mice, Knockout; Nephritis; PPAR alpha; Phagocytosis; RNA, Small Interfering; Receptors, Cholecystokinin; Signal Transduction; Ureteral Obstruction
PubMed: 33458737
DOI: 10.1042/CS20201340 -
Nutrition, Metabolism, and... Jul 2023Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study...
BACKGROUND AND AIMS
Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings.
METHODS AND RESULTS
We evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved.
CONCLUSION
In this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.
Topics: Humans; Retrospective Studies; Hypertriglyceridemia; PPAR alpha; Benzoxazoles; Triglycerides
PubMed: 37246074
DOI: 10.1016/j.numecd.2023.02.011 -
Trends in Endocrinology and Metabolism:... Feb 2024Fasting is part of many weight management and health-boosting regimens. Fasting causes substantial metabolic adaptations in the liver that include the stimulation of... (Review)
Review
Fasting is part of many weight management and health-boosting regimens. Fasting causes substantial metabolic adaptations in the liver that include the stimulation of fatty acid oxidation and ketogenesis. The induction of fatty acid oxidation and ketogenesis during fasting is mainly driven by interrelated changes in plasma levels of various hormones and an increase in plasma nonesterified fatty acid (NEFA) levels and is mediated transcriptionally by the peroxisome proliferator-activated receptor (PPAR)α, supported by CREB3L3 (cyclic AMP-responsive element-binding protein 3 like 3). Compared with men, women exhibit higher ketone levels during fasting, likely due to higher NEFA availability, suggesting that the metabolic response to fasting shows sexual dimorphism. Here, we synthesize the current molecular knowledge on the impact of fasting on hepatic fatty acid oxidation and ketogenesis.
Topics: Male; Female; Humans; Fatty Acids, Nonesterified; Fatty Acids; Liver; Ketone Bodies; Fasting; Oxidation-Reduction; PPAR alpha
PubMed: 37940485
DOI: 10.1016/j.tem.2023.10.002 -
Journal of Biochemistry Apr 2023HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease...
HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a-deficient mice (Hnf4aΔHep mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4aΔHep mice, the expression of fatty acid oxidation-related genes, which are PPARα target genes, was increased in contrast to the decreased expression of PPARα, suggesting that Hnf4aΔHep mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4aΔHep/Ppara-/- mice, which are simultaneously deficient in HNF4α and PPARα, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4aΔHep mice, and the transactivation of PPARα target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4aΔHep mouse liver, a significant increase in transactivation was observed. In addition, the expression of Pgc1a, a coactivator of PPARs, was increased, suggesting that elevated C18:1 and Pgc1a expression could contribute to PPARα activation in Hnf4aΔHep mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4α and PPARα signaling cascade.
Topics: Animals; Mice; Hepatocyte Nuclear Factor 4; Lipid Metabolism; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 36779417
DOI: 10.1093/jb/mvad005 -
Bioorganic & Medicinal Chemistry Letters Aug 2022In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1-9 were tested in vitro using a...
Synthesis, in vitro, in silico and in vivo hypoglycemic and lipid-lowering effects of 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones mediated by dual PPAR α/γ modulation.
In current work, we prepared a series of nine 4-benzyloxy-5-benzylidene-1,3-thiazolidine-2,4-diones using a two-step pathway. Compounds 1-9 were tested in vitro using a set of three proteins recognized as important targets in diabetes and related diseases: PPARα, PPARγ, and GLUT-4. Compounds 1-3, 5, and 7 showed significant increases in the mRNA expression of PPARγ and GLUT-4, whereas compounds 1-3 did it over PPARα. Compounds 1-3 were identified as a dual PPAR α/γ modulators and were selected for evaluating the in vivo antidiabetic action at 100 mg/kg dose, being orally actives and decreasing blood glucose concentration in a hyperglycemic mice model, as well as reducing the triacylglycerides levels in normolipidemic rats. Docking and molecular dynamics studies were conducted to clarify the dual effect and binding mode of compounds 1-3 on both PPARs. Compounds 2 and 3 exhibited robust in vitro and in vivo efficacy and could be considered dual PPAR modulators with antidiabetic and antidyslipidemic effects.
Topics: Animals; Hypoglycemic Agents; Lipids; Mice; PPAR alpha; PPAR gamma; Rats; Thiazolidines
PubMed: 35598791
DOI: 10.1016/j.bmcl.2022.128804