Selective PPARγ Modulators Research Articles

The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice

Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities.

Combination of SGLT2 Inhibitor and Novel Selective PPARα Modulator, Tofogliflozin (Tofo) and Pemafibrate (Pema), Improves Survival Rate in STAM Mice as a Diabetic NASH Model

Patients with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) which is emerging as a major public health concern in the world. Nonalcoholic steatohepatits (NASH), a severe form of NAFLD, can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). To establish the effective therapeutic method for NASH, we evaluate the therapeutic potential of the combination of SGLT2 inhibitor, tofogliflozin (Tofo), and a novel selective PPARα modulator (SPPARMα), pemafibrate (Pema), in STAM mice as a diabetic animal model of NASH to HCC. STAM mice were administered Tofo and Pema from 6 weeks of age. After 3 weeks of treatment, plasma triglyceride (TG) level was tended to reduce with 0.1 mg/kg Pema monotherapy, and decreased significantly to normal level in combination with 10 mg/kg Tofo. Blood glucose (BG) level was not altered in Pema-treated group, but lowered significantly with the combination therapy. Histological analysis of the liver revealed a tendency to reduce lipid droplet size and ballooning degeneration in Pema group. The combination of Pema and Tofo exhibited the synergistic effects on lipid droplet size and ballooning significantly. Liver TG content was also decreased in mice with the combination therapy. The survival rate of control group was decreased to 10% at 22 weeks of age. STAM mice with Pema in diet showed a tendency to increase the survival rate (30%) and the combination of Pema and Tofo significantly improved the survival rates (50%) compared to control group. Also, both of treated groups markedly reduced the number of tumors in the liver. These results suggested that, in addition of lipid metabolism, glycemic control might play an important role in the treatment of NASH. Combination therapy of SGLT2 inhibitor and SPPARMα would be a potent therapeutic strategy for the treatment of NAFLD, NASH and HCC. Disclosure W. Yano: Employee; Self; Kowa Company, LTD. T. Takizawa: Employee; Self; Kowa Company, LTD. Y. Sasaki: Employee; Self; Kowa Company, Ltd. M. Asahiyama: Employee; Self; Kowa Company, Ltd.. Employee; Spouse/Partner; Kowa Company, Ltd.. W. Kamiya: None. T. Nakagawa: Employee; Self; Kowa Company, LTD. H. Yamazaki: Employee; Self; Kowa Company, LTD. K. Inoue: Employee; Self; Kowa Company, LTD. K. Mizuno: Employee; Self; Kowa Company, LTD.. J. Sakai: None. T. Kodama: Consultant; Self; Kowa Company, Ltd. T. Tanaka: Research Support; Self; Kowa Company, Ltd..

Effects of Selective PPARα Modulator K-877 on Particle Numbers of Lipoprotein Subclasses in Dyslipidemic Patients: Analysis by GP-HPLC and NMR Lipoprofile 2 and 3

GNSS multipath channel characteristics research and modeling is an important but not well-solved topic. Therefore, we conducted a series of on-field research experiments from June 2015 to August 2017 at Shanghai Lujiazui area in China to study the multipath channel model of different satellite orbits for static urban canyon environment. A wideband GNSS intermediate frequency (IF) data sampling and recording platform are built up to capture real BDS B1 and GPS L1 signal. An advanced multipath estimation algorithm software is designed to extract multipath parameters from these real signal data. More than 16,400 multipath echoes are found in the on-field experiments. Based on the data, we analyze three core parameters about multipath - delay, power and lifetime. It is found that the multipath delay follows Gamma distribution. It is verified that the multipath power-delay profile follows a log-linear decline model, and the multipath lifetime follows a quasi-exponential decrease. The model feature parameters of different orbit satellite are analyzed and compared. This research deepens our insights into multipath channel characteristics in urban canyon environment and will be helpful for the design of both GNSS receivers and simulators.

Molecular association model of PPARα and its new specific and efficient ligand, pemafibrate: Structural basis for SPPARMα

Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor involved in the regulation of lipid homeostasis and improves hypertriglyceridemia. Pemafibrate is a novel selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. Here, we computationally constructed the structure of the human PPARα in a complex with pemafibrate, along with that of hPPARα complexed with the classical fenofibrate, and studied their interactions quantitatively by using the first-principles calculations-based fragment molecular orbital (FMO) method. Comprehensive structural and protein-ligand binding elucidation along with the in vitro luciferase analysis let us to identify pemafibrate as a novel SPPARMα. Unlike known fibrate ligands, which bind only with the arm I of the Y-shaped ligand binding pocket, the Y-shaped pemafibrate binds to the entire cavity region. This lock and key nature causes enhanced induced fit in pemafibrate-ligated PPARα. Importantly, this selective modulator allosterically changes PPARα conformation to form a brand-new interface, which in turn binds to PPARα co-activator, PGC-1α, resulting in the full activation of PPARα. The structural basis for the potent effects of pemafibrate on PPARα transcriptional activity predicted by the in silico FMO methods was confirmed by in vitro luciferase assay for mutants. The unique binding mode of pemafibrate reveals a new pattern of nuclear receptor ligand recognition and suggests a novel basis for ligand design, offering cues for improving the binding affinity and selectivity of ligand for better clinical consequences. The findings explain the high affinity and efficacy of pemafibrate, which is expected to be in the clinical use soon.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, AN EMERGING POTENTIAL TARGET TO COMBAT METABOLIC DISORDER

Day-by-day metabolic disorder/syndrome (MS) falling in love with current lifestyle status of everyone especially after study age group of people. If we look carefully around us, we will see evidence is growing up of diabetic, obese, and hypertensive population regularly. In urgencies of above view extensive literature survey has been done prioritizing prevalence of metabolic disorder and peroxisome proliferator-activated receptor-gamma (PPAR-γ) as potential target protein. This review covered current status of MS emphasizing diabetes along with its management criteria. Special importance is given to PPAR-γ exploring its metabolic regulation and structural orientation for understanding ligand-protein interaction. Development of PPAR-γ agonist thiazolidinediones (TZDs) and other pharmacodynamic importance of this nuclear receptor also discussed. Being as nuclear receptor more genomics exploitation needs to be done emphasizing minimization of cardiac adverse effect. Selective PPAR modulator (SPPRM), TZDs are the master regulator of adipogenesis and angiogenesis which makes TZD more interesting topic to explore. Developmental hierarchy suggests that in a few years from now PPAR-γ won’t be in the list of double edge sword.

INT131 increases dendritic arborization and protects against Aβ toxicity by inducing mitochondrial changes in hippocampal neurons

In previous studies, we have demonstrated the beneficial effects of classic PPARγ agonists on neuroprotection against Aβ oligomer neurotoxicity in a double transgenic mouse model of Alzheimer' disease (AD). INT-131, a novel, non-thiazolidinedione compound that belongs to a new family of drugs, selective PPARγ modulators (SPPARMs), has provided an emerging opportunity for the treatment of type 2 diabetes mellitus and metabolic syndrome. However, its role in the central nervous system has not been studied. The aim of this study was to evaluate the putative neuroprotective role of INT131 in hippocampal neurons. We found that INT131 increased dendritic branching, promoted neuronal survival against Aβ amyloid, increased expression of PGC1-1α and modulated neuronal mitochondrial dynamics. Our results suggest that INT131, a drug that has been shown to be safe and effective in metabolic disorders, may constitute a new therapeutic alternative for AD.

Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator.

The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs) are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM in the context of tissue selective compound distribution and PPARγ regulation. First, 30 mg kg−1 INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg−1 rosiglitazone (RSG) in both db/db and DIO mice using the oral glucose and insulin tolerance tests. Similar to RSG, INT131 significantly increased brown adipose tissue (BAT) mass and adipocyte size and up-regulated the expression of BAT-specific genes. Compared with RSG, INT131 exhibited greater potency in inducing white adipose tissue (WAT) browning, decreasing adipocyte size, and increasing BAT-specific and function-related gene expression in subcutaneous WAT (sWAT). However, it did not induce hepatomegaly or hepatic steatosis, which is associated with lower levels of lipogenic genes expression. Pharmacokinetic analysis reveals that in contrast with RSG, INT131 shows higher Cmax, and much longer residency time (AUC0−12h), as well relatively lower elimination rate in adipose tissues and skeletal muscle, this demonstrated INT131 distributed predominantly in adipose tissue. Whereas, INT131 was less abundant in the liver. These results thus suggest that the tissue-selective distribution underlies INT131's selective PPARγ modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPARγM to address the insulin resistance of diabetes.

Renoprotective effect of a novel selective PPARα modulator K-877 in db/db mice: A role of diacylglycerol-protein kinase C-NAD(P)H oxidase pathway

ObjectiveSeveral clinical studies have shown the beneficial effects of peroxisome proliferator-activated receptor α (PPARα) agonists on diabetic nephropathy. However, the molecular mechanism is not fully understood. Here we show that K-877, a novel selective PPARα modulator, ameliorates nephropathy in db/db mice via inhibition of renal lipid content and oxidative stress. Methods and resultsK-877 (0.5mg/kg/day) was administered to db/db mice for 2 or 12weeks. Short-term treatment did not affect body weight or plasma glucose levels in db/db mice, but attenuated albuminuria, along with improvement of plasma lipid profiles, lipid content including total diacylglycerol (DAG) levels, protein kinase C (PKC) activity, NAD(P)H oxidase-4 expression, and oxidative stress markers, all of which were significantly increased in diabetic kidneys. It increased phosphorylation of 5′-AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and expression of several genes mediating fatty acid β-oxidation. In addition, long-term treatment ameliorated renal mesangial expansion in db/db mice and improved glycemic control. ConclusionsK-877 administration ameliorates diabetic nephropathy, at least in part, via inhibition of renal lipid content and oxidative stress. The underlying mechanism may be mediated by modulating the renal AMPK-ACC pathway, subsequent acceleration of fatty acid β-oxidation and inhibition of fatty acid synthesis, and thus inhibition of the DAG-PKC-NAD(P)H oxidase pathway, in addition to its systemic effect including improvement of the plasma lipid profile and glycemic control.

Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice

Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr−/−) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlr−/− mice. K-877 administration to Ldlr−/− mice efficiently increased the gene expression of PPARα and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlr−/− mice. K-877 is an attractive PPARα-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine.

Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor γ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers.

Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor?

Several large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of obesity, hepatic steatosis, and cardiovascular disease. Despite the strong correlative data demonstrating the protective role of bilirubin, the mechanism by which bilirubin can protect against these pathologies remains unknown. Bilirubin has long been known as a powerful antioxidant and also has anti-inflammatory actions, each of which may contribute to the protection afforded by increased levels. We have recently described a novel function of bilirubin as a ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), which we show specifically binds to the nuclear receptor. Bilirubin may function as a selective PPAR modulator (SPPARM) to control lipid accumulation and blood glucose. However, it is not known to what degree bilirubin activation of PPARα is responsible for the protection afforded to reduce hepatic steatosis. We hypothesize that bilirubin, acting as a novel SPPARM, increases hepatic fatty acid metabolism through a PPARα-dependent mechanism which reduces hepatic lipid accumulation and protects against hepatic steatosis and non-alcoholic fatty liver disease (NAFLD).

Selective PPAR modulators (SPPARs) may fill the need for treatment of the atherogenic dyslipidemia of insulin resistance and type 2 diabetes: Can they reduce the associated cardiac risk?

Selective PPAR modulators (SPPARs) may fill the need for treatment of the atherogenic dyslipidemia of insulin resistance and type 2 diabetes: Can they reduce the associated cardiac risk?

The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis

BackgroundAtherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. ObjectiveTo study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. Approach and resultsPemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. ConclusionsThese results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.

Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial

Background and aimsTo assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that possesses unique PPARα activity and selectivity, compared with placebo and fenofibrate in dyslipidaemic patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Methods and resultsThis study was a double blind, placebo-controlled, parallel-group 12-week clinical trial. The study randomized 224 patients to K-877 0.025, 0.05, 0.1, 0.2 mg BID, fenofibrate 100 mg QD, or placebo (1:1:1:1:1:1) groups. Least squares mean percent changes from the baseline TG levels were −30.9%, −36.4%, −42.6%, −42.7% for the K-877 0.025, 0.05, 0.1, 0.2 mg BID respectively (p < 0.001), which were greater than that of the fenofibrate 100 mg QD (−29.7%, p < 0.001) group. Statistically significant improvements from the baseline HDL-C, very-low-density lipoprotein cholesterol, chylomicron cholesterol, remnant lipoprotein cholesterol, apolipoprotein (apo) B (apoB), and apoC-III were also observed in the K-877 groups. The incidence of adverse events (AEs) in the K-877 groups (32.4–56.8%) was comparable to those in placebo (47.2%) and fenofibrate 100 mg QD (56.8%); adverse drug reactions (ADRs) in the K-877 groups (2.7–5.4%) were less than those in placebo (8.3%) and fenofibrate 100 mg QD (10.8%) groups. ConclusionIn dyslipidaemic patients with high TG and low HDL-C, K-877 improved TG, HDL-C, and other lipid parameters without increasing AEs or ADRs, compared to placebo and fenofibrate. K-877 can be expected to improve atherogenicity and to be a new beneficial treatment for dyslipidaemic patients.

Abstract 13374: Efficacy and Safety of K-877, a Potent and Selective PPAR-α Modulator (SPPARMα), in Combination With Statins in Japanese Patients With Dyslipidemia

Background: Residual cardiovascular risk remains despite intensive statin treatment. K-877, a Selective PPAR-α Modulator (SPPARMα), has shown significant reductions in atherogenic lipids with fewer adverse effects than existing PPARα agonists. We hypothesized that K-877 in combination with statins may provide further benefit and risk reduction than statins alone in patients with dyslipidemia. Methods: This is a multi-center double-blind parallel-group study. A total of 423 patients with fasting high TG (≥200 mg/dL), treated with any statins (stable dosage at least 4 weeks prior to the first screening visit) were randomized to the following 24-weeks treatment groups; placebo (n=108), twice-daily K-877 0.2 mg/day (n=150) and 0.2/0.4 mg/day [patients took 0.2 mg/day, those with TG &gt;150 mg/dL at week 8 were uptitrated to 0.4 mg/day from week 12] (n=165 [n=58]). The primary endpoint was the percentage change of TG from baseline, and rates of adverse drug reactions (ADRs) and adverse events (AEs) were assessed. Results: Fasting TG reduction was as follows; placebo: -0.8%, K-877 0.2 mg: -46.8% and K-877 0.2/0.4 mg: -50.8%. K-877 groups had significant reductions compared with placebo (P&lt;0.01). By dose titration at week 12, more patients achieved the target (fasting TG≤150 mg/dL) at week 24 (36.2% in 0.4 mg group and 29.7% in 0.2 mg group). The incidence of AEs/ADRs in K-877 groups was similar to placebo [placebo, K-877 0.2 and 0.2/0.4 mg: 57.4%/15.7%, 56.0%/19.3% and 63.6%/19.4%, respectively]. The study discontinuation rate was also similar across all dosing groups. K-877 reduced liver enzymes compared to placebo [ALT; placebo, K-877 0.2 and 0.2/0.4 mg: -0.9, -12.8 and -8.0 IU/L, respectively] and [γ-GT; -1.8, -42.6 and -40.4 IU/L, respectively]. Severe liver failure, severe renal failure or the rhabdomyolysis were not observed. Frequencies of AEs, such as CK increase and musculoskeletal and connective tissue disorders were comparable to those of placebo. Conclusions: K-877 significantly reduced TG concentrations in dyslipidemic patients on stable statin treatment, was well tolerated, and associated with reductions in liver enzymes. Thus K-877 has a favorable profile of efficacy and safety and may be useful to reduce residual risk in dyslipidemic patients.

Abstract 12384: Novel Approach to Residual Risk, K-877, a Potent and Selective PPAR-α Modulator (SPPARMα), Added-on to Pitavastatin in Japanese Patients With Dyslipidemia

Background: Residual cardiovascular risk remains despite intensive treatment with statins. K-877, a Selective PPAR-α Modulator (SPPARMα), has shown significant reductions in atherogenic lipids with fewer adverse effects than existing PPARα agonists. We hypothesized that combination with pitavastatin may provide further reduction in atherosclerotic risk, particularly in dyslipidemic patients with hypertriglyceridemia, than statin alone. Methods: This was a multi-center double-blind parallel-group study. A total of 188 patients with fasting high TG (≥200, &lt;1000 mg/dL) and non-HDL-C (≥150 mg/dL), treated with pitavastatin (once daily, 2 mg/day) were randomized to 12-week treatment groups; placebo (n=46), twice-daily K-877 0.1 (n=45), 0.2 (n=49) and 0.4 mg/day (n=48). The primary endpoint was the percentage change in TG from baseline and incidence of adverse drug reactions (ADRs) and adverse events (AEs). Results: Fasting TG reduction was as follows; placebo: -6.9%, K-877 0.1, 0.2 and 0.4 mg: -46.1%, -53.4% and -52.0%. All K-877 groups had significant reductions compared with placebo (P&lt;0.001). Fasting non-HDL-C reductions were -5.9% with placebo and -11.3, -14.1 and -13.3% with K-877 0.1, 0.2 and 0.4 mg, respectively. Significant increase in HDL-C, and reductions in VLDL-C, remnant lipoprotein cholesterol and apoCIII compared to placebo were found in all K-877 groups (P&lt;0.01). Although K-877 had a neutral effect on total LDL-C, HPLC analysis revealed a significant reduction of very small LDL-C with K-877 compared to the placebo group (P&lt;0.05). Moreover, the highest dose of K-877 (0.4 mg/day) showed significant reduction of fasting blood glucose and HOMA-R compared to placebo (P=0.003 and 0.019, respectively). The incidence of AEs and ADRs in the K-877 groups was similar to that in placebo group. The study discontinuation rates were similar across all groups. Conclusions: K-877 significantly improved plasma lipoprotein profiles in dyslipidemia patients on stable statin treatment without increasing the rates of AEs/ADRs. Thus K-877 may be a useful therapy to reduce residual cardiovascular risk in dyslipidemia.

Selective targeting of PPARγ by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency

Type 2 diabetes mellitus (T2DM) is a pervasive metabolic syndrome that is characterized by insulin resistance, hyperglycemia and dyslipidemia. As full agonists of PPARγ, thiazolidinedione (TZD) drugs elicit antidiabetic effects by targeting PPARγ but is accompanied by weight gain, fluid retention and cardiovascular risk associated with their transcriptional agonism potency. We here identify a natural product chelerythrine as a unique selective PPAR modulator (SPPARM) with a potent PPARγ binding activity but much less classical receptor transcriptional agonism. Structural analysis reveals that chelerythrine exhibits unique binding in parallel with H3 of PPARγ. Unlike TZDs, chelerythrine destabilizes helix 12, especially residue tyrosine 473, resulting in a loose configuration of AF-2 and a selective cofactor profile distinct from TZDs, leading to a differential target gene profile in adipogenesis in db/db diabetic mice. Moreover, chelerythrine improved insulin sensitivity by more potently blocking the phosphorylation of PPARγ by CDK5 compared to TZDs. These data fundamentally elucidate the mechanism by which chelerythrine retains the benefits of improving insulin sensitivity while reducing the adverse effects of TZDs, suggesting that the natural product chelerythrine is a very promising pharmacological agent by selectively targeting PPARγ for further development in the clinical treatment of insulin resistance.

Short-Chain Fatty Acids Protect Against High-Fat Diet-Induced Obesity via a PPARγ-Dependent Switch From Lipogenesis to Fat Oxidation.

Short-chain fatty acids (SCFAs) are the main products of dietary fiber fermentation and are believed to drive the fiber-related prevention of the metabolic syndrome. Here we show that dietary SCFAs induce a peroxisome proliferator-activated receptor-γ (PPARγ)-dependent switch from lipid synthesis to utilization. Dietary SCFA supplementation prevented and reversed high-fat diet-induced metabolic abnormalities in mice by decreasing PPARγ expression and activity. This increased the expression of mitochondrial uncoupling protein 2 and raised the AMP-to-ATP ratio, thereby stimulating oxidative metabolism in liver and adipose tissue via AMPK. The SCFA-induced reduction in body weight and stimulation of insulin sensitivity were absent in mice with adipose-specific disruption of PPARγ. Similarly, SCFA-induced reduction of hepatic steatosis was absent in mice lacking hepatic PPARγ. These results demonstrate that adipose and hepatic PPARγ are critical mediators of the beneficial effects of SCFAs on the metabolic syndrome, with clearly distinct and complementary roles. Our findings indicate that SCFAs may be used therapeutically as cheap and selective PPARγ modulators.

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver.

Selective PPARα modulators (SPPARMα) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARMα K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARMα on the liver gene expression. Consequently, a cell-based transactivation assay showed that K-877 activates PPARα with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid β-oxidative genes in human hepatocytes and the mouse liver. Almost all genes up- or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly induced in the K-877-treated mouse liver, but not human hepatocytes, thus suggesting that the clinical dose of K-877 may not induce peroxisome proliferation or liver toxicity in humans. Notably, K-877 significantly induces the expression of clinically beneficial target genes (VLDLR, FGF21, ABCA1, MBL2, ENPEP) in human hepatocytes. These results indicate that changes in the gene expression induced by K-877 treatment are mainly mediated through PPARα activation. K-877 regulates the hepatic gene expression as a SPPARMα and thus may improve dyslipidemia as well as metabolic disorders, such as metabolic syndrome and type 2 diabetes, without untoward side effects.

Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review

Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant.Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements.