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15 pages, 2843 KiB

Open AccessArticle

Investigating the Role of PPARβ/δ in Retinal Vascular Remodeling Using Pparβ/δ-Deficient Mice

by Sze Yuan Ho, Yuet Ping Kwan, Beiying Qiu, Alison Tan, Hannah Louise Murray, Veluchamy Amutha Barathi, Nguan Soon Tan, Chui Ming Gemmy Cheung, Tien Yin Wong, Walter Wahli and Xiaomeng Wang

Int. J. Mol. Sci. 2020, 21(12), 4403; https://doi.org/10.3390/ijms21124403 - 20 Jun 2020

Cited by 9 | Viewed by 3479

Abstract

Peroxisome proliferator-activated receptor (PPAR)β/δ is a member of the nuclear receptor superfamily of transcription factors, which plays fundamental roles in cell proliferation and differentiation, inflammation, adipogenesis, and energy homeostasis. Previous studies demonstrated a reduced choroidal neovascularization (CNV) in Pparβ/δ-deficient mice. [...] Read more.

Peroxisome proliferator-activated receptor (PPAR)β/δ is a member of the nuclear receptor superfamily of transcription factors, which plays fundamental roles in cell proliferation and differentiation, inflammation, adipogenesis, and energy homeostasis. Previous studies demonstrated a reduced choroidal neovascularization (CNV) in Pparβ/δ-deficient mice. However, PPARβ/δ’s role in physiological blood vessel formation and vessel remodeling in the retina has yet to be established. Our study showed that PPARβ/δ is specifically required for disordered blood vessel formation in the retina. We further demonstrated an increased arteriovenous crossover and wider venous caliber in Pparβ/δ-haplodeficient mice. In summary, these results indicated a critical role of PPARβ/δ in pathological angiogenesis and blood vessel remodeling in the retina. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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16 pages, 4241 KiB

Open AccessArticle

PPARβ/δ Agonism Upregulates Forkhead Box A2 to Reduce Inflammation in C2C12 Myoblasts and in Skeletal Muscle

by Wendy Wen Ting Phua, Wei Ren Tan, Yun Sheng Yip, Ivan Dongzheng Hew, Jonathan Wei Kiat Wee, Hong Sheng Cheng, Melvin Khee Shing Leow, Walter Wahli and Nguan Soon Tan

Int. J. Mol. Sci. 2020, 21(5), 1747; https://doi.org/10.3390/ijms21051747 - 4 Mar 2020

Cited by 14 | Viewed by 4881

Abstract

Daily activities expose muscles to innumerable impacts, causing accumulated tissue damage and inflammation that impairs muscle recovery and function, yet the mechanism modulating the inflammatory response in muscles remains unclear. Our study suggests that Forkhead box A2 (FoxA2), a pioneer transcription factor, has [...] Read more.

Daily activities expose muscles to innumerable impacts, causing accumulated tissue damage and inflammation that impairs muscle recovery and function, yet the mechanism modulating the inflammatory response in muscles remains unclear. Our study suggests that Forkhead box A2 (FoxA2), a pioneer transcription factor, has a predominant role in the inflammatory response during skeletal muscle injury. FoxA2 expression in skeletal muscle is upregulated by fatty acids and peroxisome proliferator-activated receptors (PPARs) but is refractory to insulin and glucocorticoids. Using PPARβ/δ agonist GW501516 upregulates FoxA2, which in turn, attenuates the production of proinflammatory cytokines and reduces the infiltration of CD45+ immune cells in two mouse models of muscle inflammation, systemic LPS and intramuscular injection of carrageenan, which mimic localized exercise-induced inflammation. This reduced local inflammatory response limits tissue damage and restores muscle tetanic contraction. In line with these results, a deficiency in either PPARβ/δ or FoxA2 diminishes the action of the PPARβ/δ agonist GW501516 to suppress an aggravated inflammatory response. Our study suggests that FoxA2 in skeletal muscle helps maintain homeostasis, acting as a gatekeeper to maintain key inflammation parameters at the desired level upon injury. Therefore, it is conceivable that certain myositis disorders or other forms of painful musculoskeletal diseases may benefit from approaches that increase FoxA2 activity in skeletal muscle. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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15 pages, 1777 KiB

Open AccessArticle

Effects of Dietary Anaplerotic and Ketogenic Energy Sources on Renal Fatty Acid Oxidation Induced by Clofibrate in Suckling Neonatal Pigs

by Xi Lin, Brandon Pike, Jinan Zhao, Yu Fan, Yongwen Zhu, Yong Zhang, Feng Wang and Jack Odle

Int. J. Mol. Sci. 2020, 21(3), 726; https://doi.org/10.3390/ijms21030726 - 22 Jan 2020

Cited by 1 | Viewed by 2715

Abstract

Maintaining an active fatty acid metabolism is important for renal growth, development, and health. We evaluated the effects of anaplerotic and ketogenic energy sources on fatty acid oxidation during stimulation with clofibrate, a pharmacologic peroxisome proliferator-activated receptor α (PPARα) agonist. Suckling newborn pigs [...] Read more.

Maintaining an active fatty acid metabolism is important for renal growth, development, and health. We evaluated the effects of anaplerotic and ketogenic energy sources on fatty acid oxidation during stimulation with clofibrate, a pharmacologic peroxisome proliferator-activated receptor α (PPARα) agonist. Suckling newborn pigs (n = 72) were assigned into 8 dietary treatments following a 2 × 4 factorial design: ± clofibrate (0.35%) and diets containing 5% of either (1) glycerol-succinate (GlySuc), (2) tri-valerate (TriC5), (3) tri-hexanoate (TriC6), or (4) tri-2-methylpentanoate (Tri2MPA). Pigs were housed individually and fed the iso-caloric milk replacer diets for 5 d. Renal fatty acid oxidation was measured in vitro in fresh tissue homogenates using [1-¹⁴C]-labeled palmitic acid. The oxidation was 30% greater in pig received clofibrate and 25% greater (p < 0.05) in pigs fed the TriC6 diet compared to those fed diets with GlySuc, TriC5, and Tri2MPA. Addition of carnitine also stimulated the oxidation by twofold (p < 0.05). The effects of TriC6 and carnitine on palmitic acid oxidation were not altered by clofibrate stimulation. However, renal fatty acid composition was altered by clofibrate and Tri2MPA. In conclusion, modification of anaplerosis or ketogenesis via dietary substrates had no influence on in vitro renal palmitic acid oxidation induced by PPARα activation. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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14 pages, 2370 KiB

Open AccessArticle

Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations

by Mayu Kawasaki, Akira Kambe, Yuta Yamamoto, Sundaram Arulmozhiraja, Sohei Ito, Yoshimi Nakagawa, Hiroaki Tokiwa, Shogo Nakano and Hitoshi Shimano

Int. J. Mol. Sci. 2020, 21(1), 361; https://doi.org/10.3390/ijms21010361 - 6 Jan 2020

Cited by 20 | Viewed by 6015

Abstract

The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, [...] Read more.

The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARα; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARα compared with the interaction between fenofibrate and PPARα. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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12 pages, 1740 KiB

Open AccessArticle

WY-14643 Regulates CYP1B1 Expression through Peroxisome Proliferator-Activated Receptor α-Mediated Signaling in Human Breast Cancer Cells

by Yong Pil Hwang, Seong Su Won, Sun Woo Jin, Gi Ho Lee, Thi Hoa Pham, Jae Ho Choi, Keon Wook Kang and Hye Gwang Jeong

Int. J. Mol. Sci. 2019, 20(23), 5928; https://doi.org/10.3390/ijms20235928 - 25 Nov 2019

Cited by 16 | Viewed by 3748

Abstract

Human cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endobiotics and xenobiotics plays an important role in the progression of human breast cancer. In this study, we investigated the effects of WY-14643, a peroxisome proliferator-activated receptor α (PPARα) agonist, on CYP1B1 expression and the related [...] Read more.

Human cytochrome P450 1B1 (CYP1B1)-mediated biotransformation of endobiotics and xenobiotics plays an important role in the progression of human breast cancer. In this study, we investigated the effects of WY-14643, a peroxisome proliferator-activated receptor α (PPARα) agonist, on CYP1B1 expression and the related mechanism in MCF7 breast cancer cells. We performed quantitative reverse transcription-polymerase chain reaction, transient transfection, and chromatin immunoprecipitation to evaluate the effects of PPARα on peroxisome proliferator response element (PPRE)-mediated transcription. WY-14643 increased the protein and mRNA levels of CYP1B1, as well as promoter activity, in MCF-7 cells. Moreover, WY-14643 plus GW6471, a PPARα antagonist, significantly inhibited the WY-14643-mediated increase in CYP1B1 expression. PPARα knockdown by a small interfering RNA markedly suppressed the induction of CYP1B1 expression by WY-14643, suggesting that WY-14643 induces CYP1B1 expression via a PPARα-dependent mechanism. Bioinformatics analysis identified putative PPREs (−833/−813) within the promoter region of the CYP1B1 gene. Inactivation of these putative PPREs by deletion mutagenesis suppressed the WY-14643-mediated induction of CYP1B1 promoter activation. Furthermore, WY-14643 induced PPARα to assume a form capable of binding specifically to the PPRE-binding site in the CYP1B1 promoter. Our findings suggest that WY-14643 induces the expression of CYP1B1 through activation of PPARα. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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18 pages, 1304 KiB

Open AccessArticle

Hepatic MicroRNA Expression by PGC-1α and PGC-1β in the Mouse

by Elena Piccinin, Maria Arconzo, Giusi Graziano, Michele Vacca, Claudia Peres, Elena Bellafante, Gaetano Villani and Antonio Moschetta

Int. J. Mol. Sci. 2019, 20(22), 5735; https://doi.org/10.3390/ijms20225735 - 15 Nov 2019

Cited by 3 | Viewed by 3679

Abstract

The fine-tuning of liver metabolism is essential to maintain the whole-body homeostasis and to prevent the onset of diseases. The peroxisome proliferator-activated receptor-γ coactivators (PGC-1s) are transcriptional key players of liver metabolism, able to regulate mitochondrial function, gluconeogenesis and lipid metabolism. Their activity [...] Read more.

The fine-tuning of liver metabolism is essential to maintain the whole-body homeostasis and to prevent the onset of diseases. The peroxisome proliferator-activated receptor-γ coactivators (PGC-1s) are transcriptional key players of liver metabolism, able to regulate mitochondrial function, gluconeogenesis and lipid metabolism. Their activity is accurately modulated by post-translational modifications. Here, we showed that specific PGC-1s expression can lead to the upregulation of different microRNAs widely implicated in liver physiology and diseases development and progression, thus offering a new layer of complexity in the control of hepatic metabolism. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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27 pages, 1493 KiB

Open AccessArticle

Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): Pooled Analysis of Phase 2 and 3 Studies in Dyslipidemic Patients with or without Statin Combination

by Shizuya Yamashita, Hidenori Arai, Koutaro Yokote, Eiichi Araki, Mitsunori Matsushita, Toshiaki Nojima, Hideki Suganami and Shun Ishibashi

Int. J. Mol. Sci. 2019, 20(22), 5537; https://doi.org/10.3390/ijms20225537 - 6 Nov 2019

Cited by 38 | Viewed by 5164

Abstract

Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with [...] Read more.

Hypertriglyceridemia has emerged as an independent risk factor for cardiovascular events, despite low-density lipoprotein-cholesterol (LDL-C) well-controlled with statins. We pooled data from the first 12 weeks of six randomized double-blind placebo-controlled studies of pemafibrate in Japan and investigated its efficacy and safety with and without statins, particularly focusing on patients with renal dysfunction. Subjects were 1253 patients (677 in the “with-statin” group and 576 in the “without-statin” group). At Week 12 (last observation carried forward), triglyceride (TG) was significantly reduced at all pemafibrate doses (0.1, 0.2, and 0.4 mg/day), both with and without statin, compared to placebo (p < 0.001 vs. placebo for all groups). In the “with-statin” group, the estimated percent change from baseline was −2.0% for placebo and −45.1%, −48.5%, and −50.0%, respectively, for the pemafibrate groups. Findings for both groups showed significant decreases in TG-rich lipoproteins and atherogenic lipid parameters compared to placebo. The incidence of adverse events was similar between the pemafibrate and placebo groups and was also similar for patients with and without renal dysfunction in the “with-statin” group. Pemafibrate lowered TG and improved atherogenic dyslipidemia without a significant increase in adverse events in comparison to the placebo, even among “with-statin” patients who had renal dysfunction. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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19 pages, 2530 KiB

Open AccessArticle

Complementary Immunometabolic Effects of Exercise and PPARβ/δ Agonist in the Context of Diet-Induced Weight Loss in Obese Female Mice

by Sébastien Le Garf, Joseph Murdaca, Isabelle Mothe-Satney, Brigitte Sibille, Gwenaëlle Le Menn, Giulia Chinetti, Jaap G. Neels and Anne-Sophie Rousseau

Int. J. Mol. Sci. 2019, 20(20), 5182; https://doi.org/10.3390/ijms20205182 - 19 Oct 2019

Cited by 11 | Viewed by 3860

Abstract

Regular aerobic exercise, independently of weight loss, improves metabolic and anti-inflammatory states, and can be regarded as beneficial in counteracting obesity-induced low-grade inflammation. However, it is still unknown how exercise alters immunometabolism in a context of dietary changes. Agonists of the Peroxisome Proliferator [...] Read more.

Regular aerobic exercise, independently of weight loss, improves metabolic and anti-inflammatory states, and can be regarded as beneficial in counteracting obesity-induced low-grade inflammation. However, it is still unknown how exercise alters immunometabolism in a context of dietary changes. Agonists of the Peroxisome Proliferator Activated-Receptor beta/delta (PPARβ/δ) have been studied this last decade as “exercise-mimetics”, which are potential therapies for metabolic diseases. In this study, we address the question of whether PPARβ/δ agonist treatment would improve the immunometabolic changes induced by exercise in diet-induced obese female mice, having switched from a high fat diet to a normal diet. 24 mice were assigned to groups according to an 8-week exercise training program and/or an 8-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist. Our results show metabolic changes of peripheral lymphoid tissues with PPARβ/δ agonist (increase in fatty acid oxidation gene expression) or exercise (increase in AMPK activity) and a potentiating effect of the combination of both on the percentage of anti-inflammatory Foxp3+ T cells. Those effects are associated with a decreased visceral adipose tissue mass and skeletal muscle inflammation (TNF-α, Il-6, Il-1β mRNA level), an increase in skeletal muscle oxidative capacities (citrate synthase activity, endurance capacity), and insulin sensitivity. We conclude that a therapeutic approach targeting the PPARβ/δ pathway would improve obesity treatment. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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25 pages, 5050 KiB

Open AccessArticle

The Potential of the FSP1cre-Pparb/d^−/− Mouse Model for Studying Juvenile NAFLD

by Jiapeng Chen, Yan Zhuang, Ming Keat Sng, Nguan Soon Tan and Walter Wahli

Int. J. Mol. Sci. 2019, 20(20), 5115; https://doi.org/10.3390/ijms20205115 - 15 Oct 2019

Cited by 6 | Viewed by 3761

Abstract

Non-alcoholic fatty liver disease (NAFLD) can progress from steatosis to non-alcoholic steatohepatitis (NASH) characterized by liver inflammation, possibly leading to cirrhosis and hepatocellular carcinoma (HCC). Mice with impaired macrophage activation, when fed a high-fat diet, develop severe NASH. Evidence is mounting that Kupffer [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) can progress from steatosis to non-alcoholic steatohepatitis (NASH) characterized by liver inflammation, possibly leading to cirrhosis and hepatocellular carcinoma (HCC). Mice with impaired macrophage activation, when fed a high-fat diet, develop severe NASH. Evidence is mounting that Kupffer cells are implicated. However, it is unknown whether the resident CD68⁺ or bone marrow-derived CD11b⁺ Kupffer cells are involved. Characterization of the FSP1cre-Pparb/d^−/− mouse liver revealed that FSP1 is expressed in CD11b⁺ Kupffer cells. Although these cells only constitute a minute fraction of the liver cell population, Pparb/d deletion in these cells led to remarkable hepatic phenotypic changes. We report that a higher lipid content was present in postnatal day 2 (P2) FSP1cre-Pparb/d^−/− livers, which diminished after weaning. Quantification of total lipids and triglycerides revealed that P2 and week 4 of age FSP1cre-Pparb/d^−/− livers have higher levels of both. qPCR analysis also showed upregulation of genes involved in fatty acid β-oxidation, and fatty acid and triglyceride synthesis pathways. This result is further supported by western blot analysis of proteins in these pathways. Hence, we propose that FSP1cre-Pparb/d^−/− mice, which accumulate lipids in their liver in early life, may represent a useful animal model to study juvenile NAFLD. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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13 pages, 1928 KiB

Open AccessArticle

Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

by Sharon Ann Barretto, Frédéric Lasserre, Anne Fougerat, Lorraine Smith, Tiffany Fougeray, Céline Lukowicz, Arnaud Polizzi, Sarra Smati, Marion Régnier, Claire Naylies, Colette Bétoulières, Yannick Lippi, Hervé Guillou, Nicolas Loiseau, Laurence Gamet-Payrastre, Laila Mselli-Lakhal and Sandrine Ellero-Simatos

Int. J. Mol. Sci. 2019, 20(15), 3767; https://doi.org/10.3390/ijms20153767 - 1 Aug 2019

Cited by 15 | Viewed by 5503

Abstract

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not [...] Read more.

The pregnane X receptor (PXR) is the main nuclear receptor regulating the expression of xenobiotic-metabolizing enzymes and is highly expressed in the liver and intestine. Recent studies have highlighted its additional role in lipid homeostasis, however, the mechanisms of these regulations are not fully elucidated. We investigated the transcriptomic signature of PXR activation in the liver of adult wild-type vs. Pxr^-/- C57Bl6/J male mice treated with the rodent specific ligand pregnenolone 16α-carbonitrile (PCN). PXR activation increased liver triglyceride accumulation and significantly regulated the expression of 1215 genes, mostly xenobiotic-metabolizing enzymes. Among the down-regulated genes, we identified a strong peroxisome proliferator-activated receptor α (PPARα) signature. Comparison of this signature with a list of fasting-induced PPARα target genes confirmed that PXR activation decreased the expression of more than 25 PPARα target genes, among which was the hepatokine fibroblast growth factor 21 (Fgf21). PXR activation abolished plasmatic levels of FGF21. We provide a comprehensive signature of PXR activation in the liver and identify new PXR target genes that might be involved in the steatogenic effect of PXR. Moreover, we show that PXR activation down-regulates hepatic PPARα activity and FGF21 circulation, which could participate in the pleiotropic role of PXR in energy homeostasis. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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21 pages, 2151 KiB

Open AccessArticle

Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment

by Koutaro Yokote, Shizuya Yamashita, Hidenori Arai, Eiichi Araki, Hideki Suganami and Shun Ishibashi

Int. J. Mol. Sci. 2019, 20(3), 706; https://doi.org/10.3390/ijms20030706 - 6 Feb 2019

Cited by 65 | Viewed by 6997

Abstract

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including [...] Read more.

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including those with chronic kidney disease (CKD). In this multicenter, single-arm, open-label, phase III trial, 0.2–0.4 mg/day pemafibrate was administered for 52 weeks to 189 patients with hypertriglyceridemia and an estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m² on statin or regardless of eGFR when statin was not administered. Post-hoc analyses were performed on subgroups stratified by baseline eGFR. Triglyceride levels decreased by 45.9% at week 52 (last-observation-carried-forward). These reductions were not correlated with baseline eGFR. The eGFR < 30 mL/min/1.73 m² subgroup showed the greatest reduction in chylomicron, very low-density lipoprotein, small low-density lipoprotein cholesterol levels, and an increase in high-density lipoprotein cholesterol levels. The incidences of adverse events and adverse drug reactions were 82.0% and 31.7%, respectively, and these were not associated with baseline eGFR. In CKD patients, pemafibrate blood concentrations were not elevated. Pemafibrate showed a good safety profile and efficacy in correcting lipid abnormalities in a broad range of patients, including those with CKD. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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13 pages, 2532 KiB

Open AccessArticle

Salt Induces Adipogenesis/Lipogenesis and Inflammatory Adipocytokines Secretion in Adipocytes

by Myoungsook Lee, Sungbin Richard Sorn, Yunkyoung Lee and Inhae Kang

Int. J. Mol. Sci. 2019, 20(1), 160; https://doi.org/10.3390/ijms20010160 - 4 Jan 2019

Cited by 40 | Viewed by 6702

Abstract

It is well known that high salt intake is associated with cardiovascular diseases including hypertension. However, the research on the mechanism of obesity due to high salt intake is rare. To evaluate the roles of salt on obesity prevalence, the gene expression of [...] Read more.

It is well known that high salt intake is associated with cardiovascular diseases including hypertension. However, the research on the mechanism of obesity due to high salt intake is rare. To evaluate the roles of salt on obesity prevalence, the gene expression of adipogenesis/lipogenesis and adipocytokines secretion according to adipocyte dysfunction were investigated in salt-loading adipocytes. High salt dose-dependently increased the expression of adipogenic/lipogenic genes, such as PPAR-γ, C/EBPα, SREBP1c, ACC, FAS, and aP2, but decreased the gene of lipolysis like AMPK, ultimately resulting in fat accumulation. With SIK-2 and Na⁺/K⁺-ATPase activation, salt increased the metabolites involved in the renin-angiotensin-aldosterone system (RAAS) such as ADD1, CYP11β2, and MCR. Increasing insulin dependent insulin receptor substrate (IRS)-signaling, resulting in the insulin resistance, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt-mTOR were activated but AMPK(Thr¹⁷²) was depressed in salt-loading adipocytes. The expression of pro-inflammatory adipocytokines, TNFα, MCP-1, COX-2, IL-17A, IL-6, leptin, and leptin to adiponectin ratio (LAR) were dose-dependently increased by salt treatment. Using the inhibitors of MAPK/ERK, U0126, we found that the crosstalk among the signaling pathways of MAPK/ERK, Akt-mTOR, and the inflammatory adipogenesis can be the possible mechanism of salt-linked obesity. The possibilities of whether the defense mechanisms against high dose of intracellular salts provoke signaling for adipocytes differentiation or interact with surrounding tissues through other pathways will be explored in future research. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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14 pages, 3035 KiB

Open AccessArticle

Idi1 and Hmgcs2 Are Affected by Stretch in HL-1 Atrial Myocytes

by Chih-Yuan Fang, Mien-Cheng Chen, Tzu-Hao Chang, Chia-Chen Wu, Jen-Ping Chang, Hsien-Da Huang, Wan-Chun Ho, Yi-Zhen Wang, Kuo-Li Pan, Yu-Sheng Lin, Yao-Kuang Huang, Chien-Jen Chen and Wei-Chieh Lee

Int. J. Mol. Sci. 2018, 19(12), 4094; https://doi.org/10.3390/ijms19124094 - 18 Dec 2018

Cited by 10 | Viewed by 5377

Abstract

Background: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. Methods: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight [...] Read more.

Background: Lipid expression is increased in the atrial myocytes of mitral regurgitation (MR) patients. This study aimed to investigate key regulatory genes and mechanisms of atrial lipotoxic myopathy in MR. Methods: The HL-1 atrial myocytes were subjected to uniaxial cyclic stretching for eight hours. Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism were analyzed by PCR assay (168 genes). Results: The stretched myocytes had significantly larger cell size and higher lipid expression than non-stretched myocytes (all p < 0.001). Fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism in the myocytes were analyzed by PCR assay (168 genes). In comparison with their counterparts in non-stretched myocytes, seven genes in stretched monocytes (Idi1, Olr1, Nr1h4, Fabp2, Prkag3, Slc27a5, Fabp6) revealed differential upregulation with an altered fold change >1.5. Nine genes in stretched monocytes (Apoa4, Hmgcs2, Apol8, Srebf1, Acsm4, Fabp1, Acox2, Acsl6, Gk) revealed differential downregulation with an altered fold change <0.67. Canonical pathway analysis, using Ingenuity Pathway Analysis software, revealed that the only genes in the “superpathway of cholesterol biosynthesis” were Idi1 (upregulated) and Hmgcs2 (downregulated). The fraction of stretched myocytes expressing Nile red was significantly decreased by RNA interference of Idi1 (p < 0.05) and was significantly decreased by plasmid transfection of Hmgcs2 (p = 0.004). Conclusions: The Idi1 and Hmgcs2 genes have regulatory roles in atrial lipotoxic myopathy associated with atrial enlargement. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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Review

Jump to: Research

22 pages, 916 KiB

Open AccessReview

Trace Elements, PPARs, and Metabolic Syndrome

by Yujie Shi, Yixin Zou, Ziyue Shen, Yonghong Xiong, Wenxiang Zhang, Chang Liu and Siyu Chen

Int. J. Mol. Sci. 2020, 21(7), 2612; https://doi.org/10.3390/ijms21072612 - 9 Apr 2020

Cited by 85 | Viewed by 9131

Abstract

Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace [...] Read more.

Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace elements influence the structure of proteins, enzymes, and complex carbohydrates, and thus an imbalance in trace elements is an independent risk factor for MetS. The molecular link between trace elements and metabolic homeostasis has been established, and peroxisome proliferator-activated receptors (PPARs) have appeared as key regulators bridging these two elements. This is because on one hand, PPARs are actively involved in various metabolic processes, such as abdominal adiposity and insulin sensitivity, and on the other hand, PPARs sensitively respond to changes in trace elements. For example, an iron overload attenuates hepatic mRNA expression of Ppar-α; zinc supplementation is considered to recover the DNA-binding activity of PPAR-α, which is impaired in steatotic mouse liver; selenium administration downregulates mRNA expression of Ppar-γ, thereby improving lipid metabolism and oxidative status in the liver of high-fat diet (HFD)-fed mice. More importantly, PPARs’ expression and activity are under the control of the circadian clock and show a robust 24 h rhythmicity, which might be the reasons for the side effects and the clinical limitations of trace elements targeting PPARs. Taken together, understanding the casual relationships among trace elements, PPARs’ actions, and the pathogenesis of MetS is of great importance. Further studies are required to explore the chronopharmacological effects of trace elements on the diurnal oscillation of PPARs and the consequent development of MetS. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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15 pages, 1405 KiB

Open AccessReview

PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice

by Yaping Wang, Takero Nakajima, Frank J. Gonzalez and Naoki Tanaka

Int. J. Mol. Sci. 2020, 21(6), 2061; https://doi.org/10.3390/ijms21062061 - 17 Mar 2020

Cited by 383 | Viewed by 17196

Abstract

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid [...] Read more.

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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14 pages, 473 KiB

Open AccessReview

Association of Elite Sports Status with Gene Variants of Peroxisome Proliferator Activated Receptors and Their Transcriptional Coactivator

by Miroslav Petr, Agnieszka Maciejewska-Skrendo, Adam Zajac, Jakub Chycki and Petr Stastny

Int. J. Mol. Sci. 2020, 21(1), 162; https://doi.org/10.3390/ijms21010162 - 25 Dec 2019

Cited by 23 | Viewed by 5169

Abstract

Background: Although the scientific literature regarding sports genomics has grown during the last decade, some genes, such as peroxisome proliferator activated receptors (PPARs), have not been fully described in terms of their role in achieving extraordinary sports performance. Therefore, the purpose of this [...] Read more.

Background: Although the scientific literature regarding sports genomics has grown during the last decade, some genes, such as peroxisome proliferator activated receptors (PPARs), have not been fully described in terms of their role in achieving extraordinary sports performance. Therefore, the purpose of this systematic review was to determine which elite sports performance constraints are positively influenced by PPARs and their coactivators. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used, with a combination of PPAR and sports keywords. Results: In total, 27 studies that referred to PPARs in elite athletes were included, where the Ala allele in PPARG rs1801282 was associated with strength and power elite athlete status in comparison to subelite athlete status. The C allele in PPARA rs4253778 was associated with soccer, and the G allele PPARA rs4253778 was associated with endurance elite athlete status. Other elite status endurance alleles were the Gly allele in PPARGC1A rs8192678 and the C allele PPARD rs2016520. Conclusions: PPARs can be used for estimating the potential to achieve elite status in human physical performance in strength and power, team, and aerobic sports disciplines. Carrying specific PPAR alleles can provide a partial benefit to achieving elite sports status, but does not preclude achieving elite status if they are absent. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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18 pages, 1471 KiB

Open AccessReview

Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate

by Yusuke Sasaki, Sana Raza-Iqbal, Toshiya Tanaka, Kentaro Murakami, Motonobu Anai, Tsuyoshi Osawa, Yoshihiro Matsumura, Juro Sakai and Tatsuhiko Kodama

Int. J. Mol. Sci. 2019, 20(22), 5682; https://doi.org/10.3390/ijms20225682 - 13 Nov 2019

Cited by 29 | Viewed by 5930

Abstract

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) [...] Read more.

Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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13 pages, 1053 KiB

Open AccessReview

How Epigenetic Modifications Drive the Expression and Mediate the Action of PGC-1α in the Regulation of Metabolism

by Anne I. Krämer and Christoph Handschin

Int. J. Mol. Sci. 2019, 20(21), 5449; https://doi.org/10.3390/ijms20215449 - 31 Oct 2019

Cited by 27 | Viewed by 5810

Abstract

Epigenetic changes are a hallmark of short- and long-term transcriptional regulation, and hence instrumental in the control of cellular identity and plasticity. Epigenetic mechanisms leading to changes in chromatin structure, accessibility for recruitment of transcriptional complexes, and interaction of enhancers and promoters all [...] Read more.

Epigenetic changes are a hallmark of short- and long-term transcriptional regulation, and hence instrumental in the control of cellular identity and plasticity. Epigenetic mechanisms leading to changes in chromatin structure, accessibility for recruitment of transcriptional complexes, and interaction of enhancers and promoters all contribute to acute and chronic adaptations of cells, tissues and organs to internal and external perturbations. Similarly, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is activated by stimuli that alter the cellular energetic demand, and subsequently controls complex transcriptional networks responsible for cellular plasticity. It thus is of no surprise that PGC-1α is under the control of epigenetic mechanisms, and constitutes a mediator of epigenetic changes in various tissues and contexts. In this review, we summarize the current knowledge of the link between epigenetics and PGC-1α in health and disease. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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31 pages, 366 KiB

Open AccessReview

Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs

by Michele d’Angelo, Vanessa Castelli, Maria Grazia Tupone, Mariano Catanesi, Andrea Antonosante, Reyes Dominguez-Benot, Rodolfo Ippoliti, Anna Maria Cimini and Elisabetta Benedetti

Int. J. Mol. Sci. 2019, 20(21), 5422; https://doi.org/10.3390/ijms20215422 - 31 Oct 2019

Cited by 13 | Viewed by 5874

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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21 pages, 1133 KiB

Open AccessReview

PPARγ and Cognitive Performance

by Michele d’Angelo, Vanessa Castelli, Mariano Catanesi, Andrea Antonosante, Reyes Dominguez-Benot, Rodolfo Ippoliti, Elisabetta Benedetti and Annamaria Cimini

Int. J. Mol. Sci. 2019, 20(20), 5068; https://doi.org/10.3390/ijms20205068 - 12 Oct 2019

Cited by 40 | Viewed by 5300

Abstract

Recent findings have led to the discovery of many signaling pathways that link nuclear receptors with human conditions, including mental decline and neurodegenerative diseases. PPARγ agonists have been indicated as neuroprotective agents, supporting synaptic plasticity and neurite outgrowth. For these reasons, many PPARγ [...] Read more.

Recent findings have led to the discovery of many signaling pathways that link nuclear receptors with human conditions, including mental decline and neurodegenerative diseases. PPARγ agonists have been indicated as neuroprotective agents, supporting synaptic plasticity and neurite outgrowth. For these reasons, many PPARγ ligands have been proposed for the improvement of cognitive performance in different pathological conditions. In this review, the research on this issue is extensively discussed. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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69 pages, 1936 KiB

Open AccessReview

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

by Hong Sheng Cheng, Wei Ren Tan, Zun Siong Low, Charlie Marvalim, Justin Yin Hao Lee and Nguan Soon Tan

Int. J. Mol. Sci. 2019, 20(20), 5055; https://doi.org/10.3390/ijms20205055 - 11 Oct 2019

Cited by 190 | Viewed by 16477

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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14 pages, 264 KiB

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Impact of PPAR-Alpha Polymorphisms—The Case of Metabolic Disorders and Atherosclerosis

by Massimiliano Ruscica, Marco Busnelli, Enrico Runfola, Alberto Corsini and Cesare R. Sirtori

Int. J. Mol. Sci. 2019, 20(18), 4378; https://doi.org/10.3390/ijms20184378 - 6 Sep 2019

Cited by 22 | Viewed by 5846

Abstract

Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to [...] Read more.

Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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19 pages, 3742 KiB

Open AccessReview

Interactions between Host PPARs and Gut Microbiota in Health and Disease

by Arif Ul Hasan, Asadur Rahman and Hiroyuki Kobori

Int. J. Mol. Sci. 2019, 20(2), 387; https://doi.org/10.3390/ijms20020387 - 17 Jan 2019

Cited by 58 | Viewed by 11999

Abstract

The human gastrointestinal tract is inhabited by many types of microbiota, including bacteria, viruses, and fungi. Dysregulations of their microenvironment are associated with various health problems, not only limited to gastrointestinal disorders, such as inflammatory bowel disease, but to impacts beyond the intestine. [...] Read more.

The human gastrointestinal tract is inhabited by many types of microbiota, including bacteria, viruses, and fungi. Dysregulations of their microenvironment are associated with various health problems, not only limited to gastrointestinal disorders, such as inflammatory bowel disease, but to impacts beyond the intestine. For example, intestinal microbiota can affect the liver in non-alcoholic fatty liver disease, visceral adipose tissue during adipogenesis, and the heart in atherosclerosis. The factors contributing to these pathogeneses involve the gut microbiota and the effector organs of the host, and everything in between. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) are pivotal for the modulation of many of the pathogeneses mentioned above. It is, therefore, conceivable that, in the process of host-microbiota interactions, PPARs play important roles. In this review, we focus on the interactions between host PPARs in different organs and gut microbiota and their impacts on maintaining health and various diseases. Full article

(This article belongs to the Special Issue PPARs in Metabolic Regulation: Implications for Health and Disease)

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