PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARα and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARα and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARα and FAO/OXPHOS genes is downregulated, and in vivo β-oxidation rate of 3H-labeled triolein is reduced in Pkd1RC/RC mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARα, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically available PPARα agonist. Fenofibrate treatment resulted in increased expression of PPARα and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher β-oxidation rates in Pkd1RC/RC kidneys. MRI-assessed total kidney volume and total cyst volume, kidney-weight-to-body-weight ratio, cyst index, and serum creatinine levels were significantly reduced in fenofibrate-treated compared with untreated littermate Pkd1RC/RC mice. Moreover, fenofibrate treatment was associated with reduced kidney cyst proliferation and infiltration by inflammatory cells, including M2-like macrophages. Finally, fenofibrate treatment also reduced bile duct cyst number, cyst proliferation, and liver inflammation and fibrosis. In conclusion, our studies suggest that promoting PPARα activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD.

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Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

Molecular and Cellular Biology ◽

10.1128/mcb.24.20.9079-9091.2004 ◽

2004 ◽

Vol 24 (20) ◽

pp. 9079-9091 ◽

Cited By ~ 332

Author(s):

Janice M. Huss ◽

Inés Pineda Torra ◽

Bart Staels ◽

Vincent Giguère ◽

Daniel P. Kelly

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Target Genes ◽

Cellular Fatty Acid ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

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SIRT4 Represses Peroxisome Proliferator-Activated Receptor α Activity To Suppress Hepatic Fat Oxidation

Molecular and Cellular Biology ◽

10.1128/mcb.00087-13 ◽

2013 ◽

Vol 33 (22) ◽

pp. 4552-4561 ◽

Cited By ~ 84

Author(s):

Gaëlle Laurent ◽

Vincent C. J. de Boer ◽

Lydia W. S. Finley ◽

Meredith Sweeney ◽

Hong Lu ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Target Genes ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Oxidation Rates ◽

Hepatic Fat ◽

Important Regulator

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor α (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.

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Faculty Opinions recommendation of Increases in kidney volume in autosomal dominant polycystic kidney disease can be detected within 6 months.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1156979.617056 ◽

2009 ◽

Author(s):

Ron Gansevoort ◽

Ester Meijer

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Kidney Volume ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney

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Faculty Opinions recommendation of Automatic total kidney volume measurement on follow-up magnetic resonance images to facilitate monitoring of autosomal dominant polycystic kidney disease progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725764759.793510695 ◽

2015 ◽

Author(s):

Luis Ruilope ◽

Enrique Morales

Keyword(s):

Magnetic Resonance ◽

Autosomal Dominant ◽

Volume Measurement ◽

Magnetic Resonance Images ◽

Kidney Volume ◽

Polycystic Kidney ◽

Total Kidney Volume ◽

Kidney Disease Progression ◽

Autosomal Dominant Polycystic Kidney

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Aqueous Extract of Pepino Leaves Ameliorates Palmitic Acid-Induced Hepatocellular Lipotoxicity via Inhibition of Endoplasmic Reticulum Stress and Apoptosis

Antioxidants ◽

10.3390/antiox10060903 ◽

2021 ◽

Vol 10 (6) ◽

pp. 903

Author(s):

Jen-Ying Hsu ◽

Hui-Hsuan Lin ◽

Charng-Cherng Chyau ◽

Zhi-Hong Wang ◽

Jing-Hsien Chen

Keyword(s):

Fatty Acid ◽

Palmitic Acid ◽

Er Stress ◽

Lipid Accumulation ◽

Hepg2 Cells ◽

Target Genes ◽

Liver Lipid ◽

Antioxidant Response ◽

Long Chain Fatty Acid ◽

Nrf2 Expression

Saturated fatty acid is one of the important nutrients, but contributes to lipotoxicity in the liver, causing hepatic steatosis. Aqueous pepino leaf extract (AEPL) in the previous study revealed alleviated liver lipid accumulation in metabolic syndrome mice. The study aimed to investigate the mechanism of AEPL on saturated long-chain fatty acid-induced lipotoxicity in HepG2 cells. Moreover, the phytochemical composition of AEPL was identified in the present study. HepG2 cells treated with palmitic acid (PA) were used for exploring the effect of AEPL on lipid accumulation, apoptosis, ER stress, and antioxidant response. The chemical composition of AEPL was analyzed by HPLC-ESI-MS/MS. AEPL treatment reduced PA-induced ROS production and lipid accumulation. Further molecular results revealed that AEPL restored cytochrome c in mitochondria and decreased caspase 3 activity to cease apoptosis. In addition, AEPL in PA-stressed HepG2 cells significantly reduced the ER stress and suppressed SREBP-1 activation for decreasing lipogenesis. For defending PA-induced oxidative stress, AEPL promoted Nrf2 expression and its target genes, SOD1 and GPX3, expressions. The present study suggested that AEPL protected from PA-induced lipotoxicity through reducing ER stress, increasing antioxidant ability, and inhibiting apoptosis. The efficacy of AEPL on lipotoxicity was probably concerned with kaempferol and isorhamnetin derived compounds.

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Effect of tolvaptan in Japanese patients with autosomal dominant polycystic kidney disease: a post hoc analysis of TEMPO 3:4 and TEMPO Extension Japan

Clinical and Experimental Nephrology ◽

10.1007/s10157-021-02083-y ◽

2021 ◽

Author(s):

Satoru Muto ◽

Tadashi Okada ◽

Yoshiyuki Shibasaki ◽

Tatsuki Ibuki ◽

Shigeo Horie

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Kidney Volume ◽

Polycystic Kidney ◽

Efficacy Evaluation ◽

Total Kidney Volume ◽

Post Hoc Analysis ◽

Autosomal Dominant Polycystic Kidney ◽

Post Hoc

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials. Methods Patients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed. Results In patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m2) was − 3.480 in TEMPO 3:4 and − 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (− 4.287) to TEMPO-EXTJ (− 3.364), a difference of 0.923 (P = 0.0441). Conclusion The TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline.

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New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽

10.1155/2009/571365 ◽

2009 ◽

Vol 2009 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Daniela P. Foti ◽

Francesco Paonessa ◽

Eusebio Chiefari ◽

Antonio Brunetti

Keyword(s):

Insulin Receptor ◽

Target Genes ◽

Tumour Progression ◽

Antitumour Activity ◽

Peptide Hormone ◽

Nuclear Hormone Receptor ◽

Peroxisome Proliferator ◽

Preclinical Research ◽

Peroxisome Proliferator Activated Receptor ◽

Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

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Urine and Plasma Osmolality in Patients with Autosomal Dominant Polycystic Kidney Disease: Reliable Indicators of Vasopressin Activity and Disease Prognosis?

American Journal of Nephrology ◽

10.1159/000382081 ◽

2015 ◽

Vol 41 (3) ◽

pp. 248-256 ◽

Cited By ~ 6

Author(s):

Niek F. Casteleijn ◽

Debbie Zittema ◽

Stephan J.L. Bakker ◽

Wendy E. Boertien ◽

Carlo A. Gaillard ◽

...

Keyword(s):

Water Intake ◽

Plasma Osmolality ◽

Urine Osmolality ◽

Kidney Volume ◽

Polycystic Kidney ◽

Estimated Gfr ◽

Total Kidney Volume ◽

Autosomal Dominant Polycystic Kidney ◽

Crude Analysis

Background: Vasopressin plays an essential role in osmoregulation, but has deleterious effects in patients with ADPKD. Increased water intake to suppress vasopressin activity has been suggested as a potential renoprotective strategy. This study investigated whether urine and plasma osmolality can be used as reflection of vasopressin activity in ADPKD patients. Methods: We measured urine and plasma osmolality, plasma copeptin concentration, total kidney volume (TKV, by MRI) and GFR (125I-iothalamate). In addition, change in estimated GFR (eGFR) during follow-up was assessed. Results: Ninety-four patients with ADPKD were included (56 males, age 40 ± 10, mGFR 77 ± 32 ml/min/1.73 m2, TKV 1.55 (0.99-2.40) l. Urine osmolality, plasma osmolality and copeptin concentration were 420 ± 195, 289 ± 7 mOsmol/l and 7.3 (3.2-14.6) pmol/l, respectively. Plasma osmolality was associated with copeptin concentration (R = 0.54, p < 0.001), whereas urine osmolality was not (p = 0.4). In addition, urine osmolality was not associated with TKV (p = 0.3), in contrast to plasma osmolality (R = 0.52, p < 0.001) and copeptin concentration (R = 0.61, p < 0.001). Fifty-five patients were followed for 2.8 ± 0.8 years. Baseline plasma and urine osmolality were not associated with change in eGFR (p = 0.6 and p = 0.3, respectively), whereas baseline copeptin concentration did show an association with change in eGFR, in a crude analysis (St. β = -0.41, p = 0.003) and also after adjustment for age, sex and TKV (St. β = -0.23, p = 0.05). Conclusions: These data suggest that neither urine nor plasma osmolality are valid measures to identify ADPKD patients that may benefit from increasing water intake. Copeptin appears a better alternative for this purpose.

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TetR-family transcriptional repressor Thermus thermophilus FadR controls fatty acid degradation

Microbiology ◽

10.1099/mic.0.048017-0 ◽

2011 ◽

Vol 157 (6) ◽

pp. 1589-1601 ◽

Cited By ~ 27

Author(s):

Yoshihiro Agari ◽

Kazuko Agari ◽

Keiko Sakamoto ◽

Seiki Kuramitsu ◽

Akeo Shinkai

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Target Genes ◽

Thermus Thermophilus ◽

Acyl Chain ◽

Metabolic Energy ◽

Straight Chain ◽

Fatty Acid Degradation ◽

Acid Degradation

In the extremely thermophilic bacterium Thermus thermophilus HB8, one of the four TetR-family transcriptional regulators, which we named T. thermophilus FadR, negatively regulated the expression of several genes, including those involved in fatty acid degradation, both in vivo and in vitro. T. thermophilus FadR repressed the expression of the target genes by binding pseudopalindromic sequences covering the predicted −10 hexamers of their promoters, and medium-to-long straight-chain (C10–18) fatty acyl-CoA molecules were effective for transcriptional derepression. An X-ray crystal structure analysis revealed that T. thermophilus FadR bound one lauroyl (C12)-CoA molecule per FadR monomer, with its acyl chain moiety in the centre of the FadR molecule, enclosed within a tunnel-like substrate-binding pocket surrounded by hydrophobic residues, and the CoA moiety interacting with basic residues on the protein surface. The growth of T. thermophilus HB8, with palmitic acid as the sole carbon source, increased the expression of FadR-regulated genes. These results indicate that in T. thermophilus HB8, medium-to-long straight-chain fatty acids can be used for metabolic energy under the control of FadR, although the major fatty acids found in this strain are iso- and anteiso-branched-chain (C15 and 17) fatty acids.

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