Peroxisome Proliferator-activated Receptor Alpha Agonist Research Articles

Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes

BackgroundHeart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy.Methods and resultsWe used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate’s beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824–0.998).ConclusionsThe findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy.

CRGD-platelet@MnO/MSN@PPARα/LXRα Nanoparticles Improve Atherosclerosis in Rats by Inhibiting Inflammation and Reducing Blood Lipid.

Atherosclerosis (AS) is an inflammatory disease of arterial intima driven by lipids. Liver X receptor alpha (LXRα) and peroxisome proliferator-activated receptor alpha (PPARα) agonists are limited in the treatment of AS due to their off-target effects and serious side effects. Therefore, this study was designed to construct a novel nanoparticle (NP) and evaluate its mechanism of action on inflammation inhibition and lipid reduction in AS. We synthesized cRGD-platelet@MnO/MSN@PPARα/LXRα NPs (cRGD-platelet- NPs) and confirmed their size, safety, and targeting ability through various tests, including dynamic light scattering and immunofluorescence. In vivo and in vitro experiments assessed cell proliferation, apoptosis, inflammation, and plaque formation. Finally, the NF-κB signaling pathway expression in rat aorta was determined using a western blot. The synthesis of cRGD-platelet-NPs was successful; the particle size was approximately 150 nm, and the PDI was below 0.3. They could be successfully absorbed by cells, exhibiting high safety in vivo and in vitro. The cRGD-platelet-NPs successfully reduced plaque formation, improved lipid profiles by lowering LDL-cholesterol, total cholesterol, and triglycerides, and raised HDL-cholesterol levels. Additionally, they decreased inflammatory markers in the serum and aortic tissue, suggesting reduced inflammation. Immunohistochemistry and western blot analyses indicated that these NPs could not only promote M2 macrophage polarization but also suppress the NF-κB signaling pathway. The newly developed cRGD-platelet-NPs with high safety are a promising approach to AS treatment, which can regulate ABCA1, reduce the formation of AS plaques, and enhance cholesterol efflux. The mechanism may involve the suppression of the NF-κB signaling pathway.

Promotion of maturation of human pluripotent stem cell-derived cardiomyocytes via treatment with the peroxisome proliferator-activated receptor alpha agonist Fenofibrate.

As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary.

Azoles display promising anticonvulsant effects through possible PPAR-α activation

Azoles such as nafimidone, denzimol and loreclezole are known for their clinical efficacy against epilepsy, and loreclezole acts by potentiating γ-aminobutyric acid (GABA)-ergic currents. In the current study, we report a series of azole derivatives in alcohol ester and oxime ester structure showing promising anticonvulsant effects in 6 Hz and maximal electro shock (MES) models with minimal toxicity. The most promising of the series, 5f, was active in both 6 Hz and MES tests with a median effective dose (ED50) of 118.92 mg/kg in 6 Hz test and a median toxic dose (TD50) twice as high in mice. The compounds were predicted druglike and blood–brain barrier (BBB) penetrant in silico. Contrary to what was expected, the compounds showed no in vitro affinity to GABAA receptors (GABAARs) in radioligand binding assays; however, they were found structurally similar to peroxisome proliferator-activated receptors alpha (PPAR-α) agonists and predicted to show high affinity and agonist-like binding to PPAR-α in molecular docking studies. As a result, 5f emerged as a safe azole anticonvulsant with a wide therapeutic window and possible action through PPAR-α activation.

Recent advances in the treatment and delivery system of diabetic retinopathy.

Diabetic retinopathy (DR) is a highly tissue-specific neurovascular complication of type 1 and type 2 diabetes mellitus and is among the leading causes of blindness worldwide. Pathophysiological changes in DR encompass neurodegeneration, inflammation, and oxidative stress. Current treatments for DR, including anti-vascular endothelial growth factor, steroids, laser photocoagulation, and vitrectomy have limitations and adverse reactions, necessitating the exploration of novel treatment strategies. This review aims to summarize the current pathophysiology, therapeutic approaches, and available drug-delivery methods for treating DR, and discuss their respective development potentials. Recent research indicates the efficacy of novel receptor inhibitors and agonists, such as aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, peroxisome proliferator-activated receptor alpha agonists, and novel drugs in delaying DR. Furthermore, with continuous advancements in nanotechnology, a new form of drug delivery has been developed that can address certain limitations of clinical drug therapy, such as low solubility and poor penetration. This review serves as a theoretical foundation for future research on DR treatment. While highlighting promising therapeutic targets, it underscores the need for continuous exploration to enhance our understanding of DR pathogenesis. The limitations of current treatments and the potential for future advancements emphasize the importance of ongoing research in this field.

Exploration of Secondary Metabolites in Flower-Petal Annona muricata as Agonists for Peroxisome Proliferator-Activated Receptor-Alpha (PPARα) for Liver Function

The expression of PPARα in the liver is significantly increased in both non-alcoholic fatty liver disease (NAFLD) patients and experimental models. Animal studies have shown promising outcomes in improving histological conditions, such as fibrosis, through the use of PPARα agonists. This particular petal to act as agonists for PPARα. Molecular docking and Prime MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) were employed to analyze the ligand binding affinity, atomistic interactions, and protein stability. Additionally, we conducted evaluations of the identified PPARα agonist candidates to assess their toxicity and pharmacological profiles were conducted. The hit compounds exhibit favourable binding affinity and thermodynamics stability, and interact effectively with key residues in the binding site. Furthermore, the safety assessment indicates minimal to non-acute toxicity and favourable drug-like properties for these compounds. Secondary metabolites in the extract are potential drug candidate. They demonstrate drug-like properties as they adhere to the Lipinski rule.

Fenofibrate reduces glucose-induced barrier dysfunction in feline enteroids

Diabetes mellitus (DM) is a common chronic metabolic disease in humans and household cats that is characterized by persistent hyperglycemia. DM is associated with dysfunction of the intestinal barrier. This barrier is comprised of an epithelial monolayer that contains a network of tight junctions that adjoin cells and regulate paracellular movement of water and solutes. The mechanisms driving DM-associated barrier dysfunction are multifaceted, and the direct effects of hyperglycemia on the epithelium are poorly understood. Preliminary data suggest that fenofibrate, An FDA-approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist drug attenuates intestinal barrier dysfunction in dogs with experimentally-induced DM. We investigated the effects of hyperglycemia-like conditions and fenofibrate treatment on epithelial barrier function using feline intestinal organoids. We hypothesized that glucose treatment directly increases barrier permeability and alters tight junction morphology, and that fenofibrate administration can ameliorate these deleterious effects. We show that hyperglycemia-like conditions directly increase intestinal epithelial permeability, which is mitigated by fenofibrate. Moreover, increased permeability is caused by disruption of tight junctions, as evident by increased junctional tortuosity. Finally, we found that increased junctional tortuosity and barrier permeability in hyperglycemic conditions were associated with increased protein kinase C-α (PKCα) activity, and that fenofibrate treatment restored PKCα activity to baseline levels. We conclude that hyperglycemia directly induces barrier dysfunction by disrupting tight junction structure, a process that is mitigated by fenofibrate. We further propose that counteracting modulation of PKCα activation by increased intracellular glucose levels and fenofibrate is a key candidate regulatory pathway of tight junction structure and epithelial permeability.

Sıçanlarda sirkadiyen ritim bozuklukları ile ilgili çeşitli koşulların plazma ve eritrosit lipidleri üzerindeki etkileri: peroksizomal bir bakış açısı

Purpose: Lipidomics studies of sleep restriction, which is known to be associated with circadian perturbations, revealed alterations in some plasma phospholipid levels including plasmalogens which are partly synthesized in liver peroxisomes. To this end it was aimed to investigate effects of various conditions known to cause circadian rhythm disturbances on various peroxisomal parameters and to compare those effects with that of fenofibrate, a peroxisome proliferator-activated receptor alpha agonist.
 Materials and Methods: Plasmalogens and some fatty acids in erythrocyte lysates were analyzed by GC. Peroxisomal metabolites including very long chain fatty acids as well as phytanic and pristanic acids in plasma were measured by GC-MS. Immunohistological analyses by catalase antibodies were conducted on liver sections. 
 Results: All the conditions tested exhibited increased catalase immunoreactivity in liver sections compared to that of controls. Both calorie restriction, time-restricted feeding, as well as fenofibrate treatment exhibited lower C18:0 plasmalogen contents of erythrocyte lysates. As plasmalogens are known to be synthesized by peroxisomes, the present results suggest that the peroxisomal lipid content in membranes might be affected by conditions co-occuring with circadian perturbations.
 Conclusion: Shared effects of conditions associated with circadian rhythm disturbances and peroxisomal induction by fenofibrate on erythrocyte membrane lipids might indicate a link between them.

Lipidomics based on liquid chromatography-high resolution mass spectrometry reveals the protective role of peroxisome proliferator-activated receptor alpha on kidney stone formation in mice treated with glyoxylate.

Few studies have examined the relationship between lipid metabolism and kidney stone formation, particularly the role of key lipid regulatory factors in kidney stone formation. We evaluated the effect of the lipid regulatory factor-peroxisome proliferator-activated receptor alpha on the formation of renal stones in mice by injecting them with glyoxylate followed by treatment with either a peroxisome proliferator-activated receptor alpha agonist fenofibrate or an antagonist GW6471 (GW). Liquid chromatography coupled with trapped ion mobility spectrometry-quadrupole-time-of-flight mass spectrometry-based lipidomics was used to determine the lipid profile in the mouse kidneys. Histological and biochemical analyses showed that the mice injected with glyoxylate exhibited crystal precipitation and renal dysfunction. Crystallization decreased significantly in the fenofibrate group, whereas it increased significantly in the GW group. A total of 184 lipids, including fatty acyls, glycerolipids, glycerophospholipids, and sphingolipids differed significantly between the mice in the model and control groups. Peroxisome proliferator-activated receptor alpha activity negatively correlated with glyoxylate-induced kidney stone formation in mice, which may be related to improved fatty acid oxidation, maintenance of ceramide/complex sphingolipids cycle balance, and alleviation of disorder in phospholipid metabolism.

Neonatal administration of fenofibrate had no developmental programming effect on the lipid profile and relative leucocyte telomere lengths of adolescent rats fed a high-fructose diet postnatally.

Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n=119) were allocated to four groups and gavaged with either 10mL·kg-1 body mass 0.5% dimethyl sulfoxide, 100mg·kg-1 body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p>0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p<0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.

Effects of medium chain triglycerides on hepatic fatty acid oxidation in clofibrate-fed newborn piglets.

To investigate whether increasing tricarboxylic acid (TCA) cycle activity and ketogenic capacity would augment fatty acid (FA) oxidation induced by the peroxisome proliferator-activated receptor-alpha (PPARα) agonist clofibrate, suckling newborn piglets (n=54) were assigned to 8 groups following a 2 (±clofibrate)×4 (glycerol succinate [SUC], triglycerides of 2-methylpentanoic acid [T2M], valeric acid [TC5] and hexanoic acid [TC6]) factorial design. Each group was fed an isocaloric milk formula containing either 0% or 0.35% clofibrate (wt/wt, dry matter basis) with 5% SUC, T2M, TC5 or TC6 for 5d. Another 6 pigs served as newborn controls. Fatty acid oxidation was examined in fresh homogenates of liver collected on d 6 using [1-14C] palmitic acid (1 mM) as a substrate (0.265μCi/μmol). Measurements were performed in the absence or presence of L-carnitine (1mM) or inhibitors of 3-hydroxy-3-methylglutaryl-CoA synthase (L659699, 1.6μM) or acetoacetate-CoA deacylase (iodoacetamide, 50μM). Without clofibrate stimulation, 14C accumulation in CO2 was higher from piglets fed diets containing T2M and TC5 than SUC, but similar to those fed TC6. Under clofibrate stimulation, accumulation also was higher in homogenates from piglets fed TC5 than all other dietary treatments. Interactions between clofibrate and carnitine or the inhibitors were observed (P=0.0004) for acid soluble products (ASP). Invitro addition of carnitine increased 14C-ASP (P<0.0001) above all other treatments, regardless of clofibrate treatment. The percentage of 14C in CO2 was higher (P=0.0023) in TC5 than in the control group. From these results we suggest that dietary supplementation of anaplerotic and ketogenic FA could impact FA oxidation and modify the metabolism of acetyl-CoA (product of β-oxidation) via alteration of TCA cycle activity, but the modification has no significant impact on the hepatic FA oxidative capacity induced by PPARα. In addition, the availability of carnitine is a critical element to maintain FA oxidation during the neonatal period.

Hepatic fibrosis: Targeting peroxisome proliferator-activated receptor alpha from mechanism to medicines.

Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.

Provincial Fibrate Prescriptions in Older Adults With Diabetes Mellitus: A Population-based Cross-sectional Study

Fibrates are peroxisome proliferator-activated receptor-alpha agonist medications that lower triglycerides. In people with diabetes, fibrates are primarily indicated for severe hypertriglyceridemia (HTG) to reduce pancreatitis risk. Fibrates may also be considered for cardiovascular (CV) protection in those with less severe HTG at high CV risk. Beyond lipid-lowering, fibrates may also delay diabetic retinopathy progression. This population-based cross-sectional study used linked health-care databases held at ICES to examine the incidence and prevalence of fibrate prescriptions in older Ontario adults with diabetes (January 1 to December 31, 2018) and identify predictors of new fibrate prescriptions.

Fenofibrate ameliorates letrozole-induced polycystic ovary in rats via modulation of PPARα and TNFα/CD95 pathway.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine health problem during the childbearing period that seriously affects fertility in females. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, showed beneficial effects in models of endocrine disturbances. Thus, we evaluated the potential therapeutic effect of fenofibrate in experimental PCOS. Rats received oral fenofibrate (300 mg/kg/day) for three weeks following a three-week PCOS induction regimen using oral letrozole (1 mg/kg/day). We determined the changes in body weight, levels of serum testosterone, insulin, anti-Müllerian hormone (AMH), ovarian malondialdehyde (MDA), superoxide dismutase (SOD), and tissue tumor necrosis factor-alpha (TNFα) and CD95 protein expressions. The tissue expression of interleukin-10 (IL10) and PPARα genes was determined. Letrozole-treated rats showed successful induction of PCOS, confirmed by histopathology and significantly increased body weight, testosterone, insulin, AMH, and MDA, and decreased SOD. Ovaries of untreated PCOS rats showed increased TNFα and CD95 and decreased PPARα and IL10 expression. Administration of fenofibrate ameliorated the letrozole-induced PCOS changes. Fenofibrate-mediated amelioration of PCOS in rats is attributed partly to its antioxidant, anti-inflammatory, and anti-apoptotic properties and activation of PPARα.

Pemafibrate Prevents Rupture of Angiotensin II-Induced Abdominal Aortic Aneurysms.

BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture.MethodsExperimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE–/– mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).ResultsThe size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate.ConclusionPemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.

Possible Role of Ppar-Alpha Agonist in Attenuated Cardioprotective Effects of Ischemic Postconditioning in Diabetic Rat Heart

Background: It has been accounted for that infarct size reduction and cardioprotective effects of Ischemic Postconditioning (IPOC) have been abrogated in few pathological conditions including diabetes. Peroxisome Proliferator-Activated Receptor-Alpha (PPAR-Alpha) agonist is known to have cardioprotective effect. Therefore, the current examination researched the possible role of PPAR-Alpha Agonist in Attenuated Cardioprotective Effects of Ischemic Postconditioning in Diabetic Rat Heart. Materials and Methods: Rats were injected Alloxan Monohydrate (150/mg/kg/i.p) single dose to produced diabetes. Isolated Langendorff ’s perfused normal and diabetic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analyzed for Lactatedehydogenase (LDH) and Creatine Kinase (CK) release to evaluate the extent of cardiac injury. The oxidative stress in heart was evaluated by measuring Thiobarbituric Acid Reactive Substances (TBARS), superoxide dismutase (SOD) generation and reduced form of glutathione. Result: In the current investigation, Ischemia-reperfusion (I/R) induced oxidative stress by increasing TBARS, superoxide anion generation and the decreased form of glutathione in normal and diabetic rat heart. Moreover, I/R induced myocardial injury, was evaluated in terms of increase in, LDH and CK release in coronary effluent, and reduction in coronary flow rate in normal and diabetic rat heart. The diabetic rat heart showed enhanced I/R induced myocardial injury with high extent of oxidative stress as compared with normal rat heart subjected to I/R Six episodes of IPOC afforded cardioprotection against I/R induced myocardial injury in normal rat heart as assessed in terms of improvement of coronary flow rate and decrease of LDH, CK and oxidative stress. On other hand, IPOC mediated myocardial protection against I/R injury was nullified in diabetic rat heart. Fenofibrate (5µM), a selective agonist of PPAR alpha, its administration markedly restored the Cardioprotective potential of IPOC in diabetic rat heart. Conclusion: The current investigation presumed that, the high degree of oxidative stress produced in diabetic rat heart during reperfusion and resulting inactivation of PPAR alpha receptor might be responsible for abolishing the Cardioprotective potential of IPOC against I/R induced myocardial injury

Effect of type 2 diabetes on A disintegrin and metalloprotease 10.

BackgroundAs a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin‐like oxidized low‐density lipoprotein receptor 1 (LOX‐1), can be influenced by type 2 diabetes.MethodsA total of 1091 individuals with type 2 diabetes and 358 age‐matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX‐1 (sLOX‐1) released by cleavage of LOX‐1 by ADAM were measured by enzyme‐linked immunosorbent assay kits (ELISA).ResultsSerum ADAM10 was increased in subjects with diabetes compared with control (40.5 ng/mL [22.3‐65.7] vs 10.3 ng/mL [7.0‐17.9], respectively; P < .01); the highest levels were seen in insulin‐treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX‐1. Subjects with diabetes had higher serum sLOX‐1 than the control (110 pg/mL [89‐153] vs 104 pg/mL [85‐138], respectively; P < .01), and there was a significant correlation between serum ADAM10 and sLOX‐1 (r = 0.26, P < .01).ConclusionsSerum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker.

Proximal Tubule‐Specific Transgenic Overexpression of Peroxisome Proliferator‐Activated Receptor Alpha Prevents the Development of Hypertension in Dahl Salt‐Sensitive Rats

The Dahl salt‐sensitive rat (Dahl SS) is a well investigated model of hypertension that mimics human salt sensitive hypertension. These rats develop a significant increase in blood pressure and renal disease when challenged with a high salt diet compared to salt‐resistant strains. Prolonged high salt feeding results in extensive renal pathology, including glomerular and proximal tubular pathology, tubular casting, and interstitial fibrosis. It has been shown that clofibrate, a lipid lowering peroxisome proliferator‐activated receptor alpha (PPARα) agonist, can prevent the hypertensive phenotype in Dahl SS rats. PPARα is a ligand activated transcription factor that regulates β‐oxidation of fatty acids (FAO). The proximal tubule is a very metabolically active tubular segment that relies primarily on FAO to meet its high energy requirements. Reduced FAO can lead to proximal tubular damage and renal dysfunction. To investigate the impact of PPARα‐mediated FAO during a high‐salt challenge, we developed a novel transgenic Dahl SS strain with a proximal tubule‐specific promoter from the sodium/glucose cotransporter 2 gene (Sglt2). This resulted in the overexpression of Ppara only in the proximal tubule (SSTgPTPpara). At 9 weeks of age, male wild‐type rats and heterozygous transgenic SSTgPTPpara rats were placed on a 4.0% NaCl, high salt diet (n=6/group). Following a 14‐day high salt challenge, rats were anesthetized for carotid blood pressure recording. Proximal tubule‐specific transgenic overexpression of PPARα in heterozygous SSTgPTPpararats had lower systolic blood pressure when compared to wild‐type littermates (161.2.6 ± 12.0 mmHg vs.122.8 ± 4.2 mmHg; mean ± SEM; p &lt;0.05, t‐test), as well as mean arterial pressure and diastolic blood pressure. Immunohistochemical analysis confirmed an increase in PPARA protein within proximal tubules of the renal cortex, relative to other nephron segments. In conclusion, proximal tubule specific‐transgenic overexpression of PPARα reduced salt‐sensitive hypertension, suggesting that proximal tubules may be one of the primary sites of anti‐hypertensive actions of clofibrate in Dahl SS rats. This also indicates that the SSTgPTPpara rat model could be useful for studying the contribution of dysregulated proximal tubule metabolism to salt‐sensitive hypertension and renal pathology in the Dahl SS rat.

Molecular Biological and Clinical Understanding of the Statin Residual Cardiovascular Disease Risk and Peroxisome Proliferator-Activated Receptor Alpha Agonists and Ezetimibe for Its Treatment.

Several randomized, double blind, placebo-controlled trials (RCTs) have demonstrated that low-density lipoprotein cholesterol (LDL-C) lowering by using statins, including high-doses of strong statins, reduced the development of cardiovascular disease (CVD). However, among the eight RCTs which investigated the effect of statins vs. placebos on the development of CVD, 56–79% of patients had the residual CVD risk after the trials. In three RCTs which investigated the effect of a high dose vs. a usual dose of statins on the development of CVD, 78–87% of patients in the high-dose statin arms still had the CVD residual risk after the trials. An analysis of the characteristics of patients in the RCTs suggests that elevated triglyceride (TG) and reduced high-density lipoprotein cholesterol (HDL-C), the existence of obesity/insulin resistance, and diabetes may be important metabolic factors which determine the statin residual CVD risk. To understand the association between lipid abnormalities and the development of atherosclerosis, we show the profile of lipoproteins and their normal metabolism, and the molecular and biological mechanisms for the development of atherosclerosis by high TG and/or low HDL-C in insulin resistance. The molecular biological mechanisms for the statin residual CVD risk include an increase of atherogenic lipoproteins such as small dense LDL and remnants, vascular injury and remodeling by inflammatory cytokines, and disturbed reverse cholesterol transport. Peroxisome proliferator-activated receptor alpha (PPARα) agonists improve atherogenic lipoproteins, reverse the cholesterol transport system, and also have vascular protective effects, such as an anti-inflammatory effect and the reduction of the oxidative state. Ezetimibe, an inhibitor of intestinal cholesterol absorption, also improves TG and HDL-C, and reduces intestinal cholesterol absorption and serum plant sterols, which are increased by statins and are atherogenic, possibly contributing to reduce the statin residual CVD risk.

Oleoylethanolamide Alleviates Hepatic Ischemia-Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress-Associated Apoptosis.

Liver ischemia/reperfusion (I/R) injury is a primary complication in major liver surgery. Our previous study about proteome profiling has revealed that the PPAR signaling cascade was significantly upregulated during liver ischemia/reperfusion. To elucidate the potential mechanisms of PPARα involved in I/R injury, we used oleoylethanolamide (OEA), the peroxisome proliferator-activated receptor alpha (PPARα) agonist, in this study. We demonstrated a protective role of OEA on liver I/R injury by using a mouse model of partial warm ischemia-reperfusion and hypoxia-reoxygenation model of hepatocytes. These effects were caused by ameliorating liver damage, decreasing the level of serum ALT and AST, and reducing the apoptosis of hepatocytes. Furthermore, a mechanistic study revealed that OEA regulated endoplasmic reticulum (ER) stress by activating PPARα, thereby reducing ER stress-associated apoptosis to attenuate liver I/R injury. Briefly, these data first proposed that OEA-mediated PPARα activation could be an effective therapy against hepatic ischemia/reperfusion injury.