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Background: As the second most risky environmental pollution, noise imposes threats to human health. Exposure to high-intensity noise causes hearing impairment, psychotic disorders, endocrine modifications. The relationship among low-intensity noise, obesity and lipid-regulating nuclear factor PPARα is not yet clear., Methods: In this study, male wild-type (WT) and Pparα-null (KO) mice on a high-fat diet (HFD) were exposed to 75 dB noise for 12 weeks to explore the effect of low-intensity noise on obesity development and the role of PPARα. 3T3-L1 cells were treated with dexamethasone (DEX) and sodium oleate (OA) to verify the down-stream effect of hypothalamic-pituitary-adrenal (HPA) axis activation on the adipose tissues., Results: The average body weight gain (BWG) of WT mice on HFD exposed to noise was inhibited, which was not observed in KO mice. The mass and adipocyte size of adipose tissues accounted for the above difference of BWG tendency. In WT mice on HFD, the adrenocorticotropic hormone level was increased by the noise challenge. The aggravation of fatty liver by noise exposure occurred in both mouse lines, and the transport of hepatic redundant lipid to adipose tissues were similar. The lipid metabolism in adipose tissue driven by HPA axis accorded with the BWG inhibition in vivo, validated in 3T3-L1 adipogenic stem cells., Conclusion: Chronic exposure to low-intensity noise aggravated fatty liver in both WT and KO mice. BWG inhibition was observed only in WT mice, which covered up the aggravation of fatty liver by noise exposure. PPARα mediates the activation of HPA axis by noise exposure in mice on HFD. Elevated adrenocorticotropic hormone (ACTH) promoted lipid metabolism in adipocytes, which contributed to the disassociation of BWG and fatty liver development in male WT mice. Summary of PPARα suppresses noise-induced body weight gain in mice on high-fat-diet. Chronic exposure to low-intensity noise exposure inhibited BWG by PPARα-dependent activation of the HPA axis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Platelet hyperreactivity and increased atherothrombotic risk are specifically associated with dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARα) is an important regulator of lipid metabolism. It has been suggested to affect both thrombosis and hemostasis, yet the underlying mechanisms are not well understood. In this study, the role and mechanism of PPARα in platelet activation and thrombosis related to dyslipidemia were examined. Employing mice with deletion of PPARα (Pparα-/-), we demonstrated that PPARa is required for platelet activation and thrombus formation. The effect of PPARα is critically dependent on platelet dense granule secretion, and is contributed by p38MAPK/Akt, fatty acid b-oxidation, and NAD(P)H oxidase pathways. Importantly, PPARα and the associated pathways mediated a prothrombotic state induced by a high-fat diet and platelet hyperactivity provoked by oxidized low density lipoproteins. Platelet reactivity was positively correlated with the levels of expression of PPARα, as revealed by data from wild-type, chimeric (Pparα+/-), and Pparα-/- mice. This positive correlation was recapitulated in platelets from hyperlipidemic patients. In a lipid-treated megakaryocytic cell line, the lipid-induced reactive oxygen species-NF-kB pathway was revealed to upregulate platelet PPARα in hyperlipidemia. These data suggest that platelet PPARα critically mediates platelet activation and contributes to the prothrombotic status under hyperlipidemia.

Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara- null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Metabolic syndrome (MS) is the concurrence of at least three of five medical conditions: obesity, high blood pressure, insulin resistance, high serum triglyceride (TG) and low serum high-density lipoprotein levels. While fibrates are used to treat disorders other than the lowering serum TG, the mechanism by which fibrates decrease MS has not been established., Methods: In this study, wild-type and Ppara-null mice fed a medium-fat diet (MFD) were administered gemfibrozil and fenofibrate for 3 months respectively, to explore the effect and action mechanism., Key Findings: In Ppara-null mice, MFD treatment increased body weight, adipose tissue, serum TG and impaired glucose tolerance. These phenotypes were attenuated in two groups treated with gemfibrozil and fenofibrate. The STAT3 pathway was activated in adipose and hepatic tissues in positive control, and inhibited in groups treated with gemfibrozil and fenofibrate. The above phenotypes and inflammation were not observed in any wild-type group. In 3T3-L1 adipogenic stem cells treated with high glucose, STAT3 knockdown greatly decreased the number of lipid droplets., Conclusions: Low dose of clinical fibrates was effective against MS development independent of PPARα, and this action was mediated by STAT3 signalling inhibition in adipose tissue and, to a lesser extent, in hepatic tissues., (© 2018 Royal Pharmaceutical Society.)

α-Naphthylisothiocyanate (ANIT) is an experimental agent used to induce intrahepatic cholestasis. The Ppara-null mouse line is widely employed to explore the physiological and pathological roles of PPARα. However, little is known about how PPARα influences the hepatotoxicity of ANIT. In the present study, wild-type and Ppara-null mice were orally treated with ANIT to induce cholestasis. The serum metabolome of wild-type mice segregated from that of the Ppara-null mice, driven by changes of bile acid (BA) metabolites. Alkaline phosphatase and total BAs were elevated preferentially in Ppara-null mice, which correlated with changes in Cyp7a1, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5 genes and showed cross-talk between basal PPARα and potentially adaptive pathways. Il6, Tnfa, and target genes in the STAT3 pathway ( Socs3, Fga, Fgb, and Fgg) were up-regulated in Ppara-null mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-κB and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPARα involves regulation of BA metabolism and inhibition of NF-κB/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPARα, caution should be exercised when one attempts to draw conclusions in which the PPARα is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies.

Background and Purpose: Fenofibrate, a PPARα agonist, is the most widely prescribed drug for treating hyperlipidaemia. Although fibrate drugs are reported to be beneficial for cholestasis, their underlying mechanism has not been determined., Experimental Approach: Wild-type mice and Pparα-null mice were pretreated orally with fenofibrate for 3 days, following which α-naphthylisothiocyanate (ANIT) was administered to induce cholestasis. The PPARα agonist WY14643 and JNK inhibitor SP600125 were used to determine the role of PPARα and the JNK pathway, respectively, in cholestatic liver injury. The same fenofibrate regimen was applied to investigate its beneficial effects on sclerosing cholangitis in a DDC-induced cholestatic model., Key Results: Fenofibrate, 25 mg·kg -1 twice a day, totally attenuated ANIT-induced cholestasis and liver injury as indicated by biochemical and histological analyses. This protection occurred in wild-type, but not in Pparα-null, mice. Alterations in bile acid synthesis and transport were found to be an adaptive response rather than a direct effect of fenofibrate. WY14643 attenuated ANIT-induced cholestasis and liver injury coincident with inhibition of JNK signalling. Although SP600125 did not affect cholestasis, it inhibited liver injury in the ANIT model when the dose of fenofibrate used was ineffective. Fenofibrate was also revealed to have a beneficial effect in the sclerosing cholangitis model., Conclusions and Implications: These data suggest that the protective effects of fenofibrate against cholestasis-induced hepatic injury are dependent on PPARα and fenofibrate dose, and are mediated through inhibition of JNK signalling. This mechanism of fenofibrate protection against intrahepatic cholestasis may offer additional therapeutic opportunities for cholestatic liver diseases., (© 2017 The British Pharmacological Society.)

Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

While gemfibrozil and fenofibrate are prescribed for anti-dyslipidemia treatment, a rational basis for the use of these drugs for treatment of dyslipidemia with concurrent metabolic syndrome has not been established. In this study, wild-type and Pparα-null mice were fed gemfibrozil- or fenofibrate-containing diets for 14 days. Urine output (24 h) was monitored, and urine, serum, and liver and kidney tissues were subjected to toxicity assessment. A 2-month challenge followed by a 2-week wash-out was performed for gemfibrozil to determine urine output and the potential toxicity. A therapeutically equivalent dose of gemfibrozil was more effective than fenofibrate in increasing urine output. This regulatory effect was not observed in Pparα-null mice. In contrast, hepatomegaly induced by fenofibrate was more pronounced than that of gemfibrozil. No significant toxicity was observed in liver or kidney in the 2-month treatment with gemfibrozil. These data demonstrated PPARα mediates the increased urine output by fibrates. Considering the relative action on hepatomegaly and the regulatory effect on urine output, gemfibrozil may be the preferable drug to increase urine output. These results revealed a new pharmacodynamic effect of clinically prescribed PPARα agonists and suggested the potential value of gemfibrozil in modification of blood pressure.

Perfluorodecanoic acid (PFDA) is widely used in production of many daily necessities based on their surface properties and stability. It was assigned as a Persistent Organic Pollutant in 2009 and became a public concern partly because of its potential for activation of the peroxisome proliferator-activated receptor alpha (PPARα). In this study, wild-type and Ppara-null mice were administered PFDA (80 mg/kg). Blood and liver tissues were collected and subjected to systemic toxicological and mechanistic analysis. UPLC-ESI-QTOFMS-based metabolomics was used to explore the contributing components of the serum metabolome that led to variation between wild-type and Pparα-null mice. Bile acid homeostasis was disrupted, and slight hepatocyte injury in wild-type mice accompanied by adaptive regulation of bile acid synthesis and transport was observed. The serum metabolome in wild-type clustered differently from that in Pparα-null, featured by sharp increases in bile acid components. Differential toxicokinetic tendency was supported by regulation of UDP-glucuronosyltransferases dependent on PPARα, but it did not contribute to the hepatotoxic responses. Increase in Il-10 and activation of the JNK pathway indicated inflammation was induced by disruption of bile acid homeostasis in wild-type mice. Inhibition of p-p65 dependent on PPARα activation by PFDA stopped the inflammatory cascade, as indicated by negative response of Il-6, Tnf-α, and STAT3 signaling. These data suggest disruptive and protective role of PPARα in hepatic responses induced by PFDA.

Background: Concurrence of high glucose or diabetes in patients with dyslipidemia is presenting major challenges for clinicians. Although sporadically reported, a rational basis for the use of fibrates for the treatment of dyslipidemia with concurrent metabolic syndrome has not been established., Methods: In this study, wild-type (WT) and Ppara-null (KO) mice were fed a serial gemfibrozil- and fenofibrate-containing diet under the same experimental conditions for 14 days. Glucose level in the blood, glycogen storage in the liver tissues, and the potential toxic responses were assayed. Genes involved in glucose metabolism were determined by quantitative polymerase chain reaction analysis., Results: Both the blood glucose level and the glycogen content in the liver were down-regulated by gemfibrozil but not by fenofibrate in WT mice, in a dose-dependent manner. This decrement did not occur in KO mice for either fibrate agent. Secondary regulation on the transcription of pyruvate kinase, and gluconolactonase were observed following gemfibrozil treatment, which was differential between WT mice and KO mice., Conclusions: Gemfibrozil, not fenofibrate, down-regulates systemic glucose level and glycogen storage in the liver dependent on PPARα, suggesting its potential value for treatment of dyslipidemia with concurrent diabetes or high glucose levels.

Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.