Activation Of Peroxisome Proliferator-activated Receptor Alpha Research Articles

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

BackgroundDiverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk.Data synthesisHerein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.ConclusionsOur review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.

Cardiac peroxisome proliferator-activated receptor-α activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss

Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically at the transcriptional level owing to FA activation of peroxisome proliferator-activated receptor-alpha (PPARalpha). However, in vivo administration of PPARalpha ligands has not been shown to increase cardiac FA oxidation. In this study we have examined the cardiac response to in vivo administration of tetradecylthioacetic acid (TTA, 0.5% w/w added to the diet for 8 days), a PPAR agonist with primarily PPARalpha activity.Despite the fact that TTA treatment decreased plasma concentrations of lipids [FA and triacylglycerols (TG)], hearts from TTA-treated mice showed increased mRNA expression of PPARalpha target genes. Cardiac substrate utilization, ventricular function, cardiac efficiency, and susceptibility to ischaemia-reperfusion were examined in isolated perfused hearts. In accordance with the mRNA changes, myocardial FA oxidation was increased 2.5-fold with a concomitant reduction in glucose oxidation. This increase in FA oxidation was abolished in PPARalpha-null mice. Thus, it appears that the metabolic effects of TTA on the heart must be owing to a direct stimulatory effect on cardiac PPARalpha. Hearts from TTA-treated mice also showed a marked reduction in cardiac efficiency (because of a two-fold increase in unloaded myocardial oxygen consumption) and decreased recovery of ventricular contractile function following low-flow ischaemia.This study for the first time observed that in vivo administration of a synthetic PPARalpha ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischaemic functional recovery.

Isohumulones, the bitter component of beer, improve hyperglycemia and decrease body fat in Japanese subjects with prediabetes

A recent study reported that isohumulones, the bitter component of beer, activate peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma in vitro and decrease plasma glucose and lipid levels in diabetic mice. This study was to investigate the efficacy and safety of isohumulones for subjects with prediabetes. Ninety-four subjects with prediabetes were randomly divided into four groups. A 12-week double-blind dose-finding study was performed in which subjects ingested placebo capsules or test capsules containing 16 mg, 32 mg or 48 mg of isohumulones per day. After treatment, fasting blood glucose was decreased in the 32 mg and 48 mg groups after 4 weeks, but did not change in the placebo group. HbA1c was also significantly decreased after 4 weeks in the 16 mg group and after 8 weeks in the 32 mg and 48 mg groups. Body mass index (BMI) was significantly decreased in the 48 mg group as compared with the placebo group at 12 weeks. The decrease in total fat area was also significantly greater in the 48 mg group than in the placebo group at 12 weeks. The present study suggests that ingestion of isohumulones has beneficial effects in diabetes and obesity.

Efficacy of gemfibrozil in the primary prevention of atrial fibrillation in a large randomized controlled trial

Peroxisome proliferator-activated receptor alpha (PPARalpha) activators reduce inflammation and oxidative stress. Inflammation plays an important role in the initiation and maintenance of atrial fibrillation (AF). It has been suggested that PPARalpha activators may have antiarrhythmic properties, but no clinical data exist. The objective of this study was to investigate whether the PPARalpha activator gemfibrozil prevents or delays the development of AF in patients with coronary heart disease. We retrospectively analyzed the electrocardiograms (ECGs) performed in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial, a multicenter, randomized, double-blinded, secondary prevention trial of gemfibrozil and matching placebo. The ECGs were performed annually or biannually and when clinically indicated. Participants who were in AF on baseline ECG were excluded from the present analysis. Relative risk for AF was calculated from Cox regression with death as a competing risk factor. A total of 12,605 ECGs from 2,130 participants were interpreted (5.9 +/- 2.1 ECGs per participant, range 2-20). At baseline, the gemfibrozil (n = 1,070) and placebo (n = 1,060) groups were well matched. Mean age was 64.1 +/- 7.1 years. Over 4.4 +/- 1.5 years of follow-up, 123 (5.8%) participants developed new AF. There was no difference in AF incidence between the gemfibrozil and placebo groups (64/1,070 vs 59/1,060, respectively; P = .33). In Cox regression, the risk of AF was similar between the 2 study groups (hazard ratio 1.04, 95% CI 0.73-1.49, P = .82). In this post hoc analysis of a multicenter, double-blinded, randomized controlled trial, the PPARalpha activator gemfibrozil did not reduce the 4-year incidence of AF among men with coronary heart disease.

Gene expression profiling in the liver and lung of perfluorooctane sulfonate-exposed mouse fetuses: Comparison to changes induced by exposure to perfluorooctanoic acid

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are environmental contaminants found in the tissues of humans and wildlife. They are activators of peroxisome proliferator-activated receptor-alpha (PPARα) and exhibit hepatocarcinogenic potential in rats. PFOS and PFOA are also developmental toxicants in rodents and PFOS has been shown to induce pulmonary deficits in rat offspring. Pregnant CD-1 mice were dosed with 0, 5, or 10mg/kg PFOS from gestation days 1–17. Transcript profiling was conducted on the fetal liver and lung. Results were contrasted to data derived from a previous PFOA study. PFOS-dependent changes were primarily related to activation of PPARα. No remarkable differences were found between PFOS and PFOA. Given that PPARα signaling is required for neonatal mortality in PFOA-treated mice but not those exposed to PFOS, the neonatal mortality observed for PFOS may reflect functional deficits related to the physical properties of the chemical rather than to transcript alterations.

Molecular Mechanisms of Alcoholic Fatty Liver

Alcoholic fatty liver is a potentially pathologic condition which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. Alcohol exposure may induce fatty liver by increasing NADH/NAD(+) ratio, increasing sterol regulatory element-binding protein-1 (SREBP-1) activity, decreasing peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity, and increasing complement C3 hepatic levels. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-alpha (TNF-alpha) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity, whereas betaine and pioglitazone may attenuate fatty liver by down-regulating SREBP-1 activity. PPAR-alpha agonists have potentials to attenuate alcoholic fatty liver. Adiponectin and interleukin-6 may attenuate alcoholic fatty liver by up-regulating PPAR-alpha and insulin signaling pathways while down-regulating SREBP-1 activity and suppressing TNF-alpha production. Recent studies show that paracrine activation of hepatic cannabinoid receptor 1 by hepatic stellate cell-derived endocannabinoids also contributes to the development of alcoholic fatty liver. Furthermore, oxidative modifications and inactivation of the enzymes involved in the mitochondrial and/or peroxisomal beta-oxidation of fatty acids could contribute to fat accumulation in the liver.

Sleep deprivation increases oleoylethanolamide in human cerebrospinal fluid.

This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12 months. We found increased levels of oleoylethanolamide in CSF (P = 0.011) but not in serum (P = 0.068) after 24 h of sleep deprivation. Oleoylethanolamide is an endogenous lipid messenger that is released after neural injury and activates peroxisome proliferator-activated receptor-α (PPAR-α) with nanomolar potency. Exogenous PPAR-α agonists, such as hypolipidemic fibrates and oleoylethanolamide, exert both neuroprotective and neurotrophic effects. Thus, our results suggest that oleoylethanolamide release may represent an endogenous neuroprotective signal during sleep deprivation.

Angiotensin II downregulates the fatty acid oxidation pathway in adult rat cardiomyocytes via release of tumour necrosis factor-α

Advanced heart failure is often associated with reduced myocardial fatty acid oxidation capacity. We have previously observed that failing hearts of mice with overexpression of angiotensinogen in the myocardium exhibit marked reduction of key regulatory proteins of fatty acid oxidation. In the present study, we determined whether exposure of adult rat cardiac (ARC) myocytes to angiotensin II (Ang II) influences expression of fatty acid translocase, muscle-type carnitine palmitoyl transferase-I, and medium-chain acyl-CoA dehydrogenase. Ang II reduced mRNA expression of the three regulatory proteins in ARC myocytes during the entire 14-days culture period. However, protein expression and palmitate oxidation rate remained unaltered for 7 days, but subsequently markedly decreased. The decrease of protein expression and of fatty acid oxidation coincided with the onset of increased protein expression of tumour necrosis factor-alpha (TNF-alpha). The effect of Ang II was completely abolished by either blocking TNF-alpha formation through inhibition of reactive oxygen species-mediated activation of nuclear factor-kappaB or by neutralizing TNF-alpha with a specific antibody. Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARbeta/delta counteracted Ang II-mediated reduction of the fatty acid oxidation pathway. Prolonged exposure of cardiac myocytes to Ang II elicits downregulation of the fatty acid oxidation pathway mediated by enhanced synthesis of TNF-alpha.

Bezafibrate at Clinically Relevant Doses Decreases Serum/Liver Triglycerides via Down-Regulation of Sterol Regulatory Element-Binding Protein-1c in Mice: A Novel Peroxisome Proliferator-Activated Receptor α-Independent Mechanism

The triglyceride-lowering effect of bezafibrate in humans has been attributed to peroxisome proliferator-activated receptor (PPAR) alpha activation based on results from rodent studies. However, the bezafibrate dosages used in conventional rodent experiments are typically higher than those in clinical use (> or =50 versus < or =10 mg/kg/day), and thus it remains unclear whether such data can be translated to humans. Furthermore, because bezafibrate is a pan-PPAR activator, the actual contribution of PPARalpha to its triglyceride-lowering properties remains undetermined. To address these issues, bezafibrate at clinically relevant doses (10 mg/kg/day; low) was administered to wild-type and Ppara-null mice, and its effects were compared with those from conventionally used doses (100 mg/kg/day; high). Pharmacokinetic analyses showed that maximum plasma concentration and area under the concentration-time curve in bezafibrate-treated mice were similar to those in humans at low doses, but not at high doses. Low-dose bezafibrate decreased serum/liver triglycerides in a PPARalpha-independent manner by attenuation of hepatic lipogenesis and triglyceride secretion. It is noteworthy that instead of PPAR activation, down-regulation of sterol regulatory element-binding protein (SREBP)-1c was observed in mice undergoing low-dose treatment. High-dose bezafibrate decreased serum/liver triglycerides by enhancement of hepatic fatty acid uptake and beta-oxidation via PPARalpha activation, as expected. In conclusion, clinically relevant doses of bezafibrate exert a triglyceride-lowering effect by suppression of the SREBP-1c-regulated pathway in mice and not by PPARalpha activation. Our results may provide novel information about the pharmacological mechanism of bezafibrate action and new insights into the treatment of disorders involving SREBP-1c.

Diabetes mellitus and prognosis after curative therapy for hepatocellular carcinoma: Alas, still grave for those who are hyperglycemic

Diabetes mellitus and prognosis after curative therapy for hepatocellular carcinoma: Alas, still grave for those who are hyperglycemic

BMP-7 protects mesangial cells from injury by polymeric IgA

Bone morphogenetic protein-7 (BMP-7) is a potential therapeutic agent for acute and chronic renal diseases. Here we found that addition of polymeric IgA, isolated from patients with IgA nephropathy, increased the synthesis of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta (TGF-beta) and fibronectin in cultured human mesangial cells, effects blunted by BMP-7. When mesangial cells were cultured with both polymeric IgA and BMP-7 there was an increase in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The activation of NF kappaB and TNF-alpha synthesis induced by polymeric IgA or TNF-alpha were downregulated by BMP-7 or rosiglitazone. BMP-7 inhibited TNF-alpha release from polymeric IgA-stimulated mesangial cells by activation of PPAR-gamma but suppressed TGF-beta release by mechanisms independent of PPAR-gamma. The expression of inhibitory Smad6 and 7 was increased whereas the expression of active Smad2 and 3 was reduced in these mesangial cells by BMP-7. Our study shows that BMP-7 ameliorates IgA nephropathy-derived polymeric IgA-induced TNF-alpha and TGF-beta synthesis in human mesangial cells through multiple mechanisms involving inhibitory Smads and PPAR-gamma.

Potential Relationship between Hepatobiliary Osteopontin and Peroxisome Proliferator–Activated Receptor α Expression following Ethanol-Associated Hepatic Injury In Vivo and In Vitro

Osteopontin (OPN) up-regulation is known to mediate hepatic inflammation in a rodent model of alcoholic liver disease (ALD) and alcohol ingestion is reported to inhibit hepatic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity leading to hepatic steatosis and inflammation. Therefore, the objective of this study was to investigate the potential relationship between the anti-inflammatory PPAR-alpha and proinflammatory OPN in rats and mice livers, and cell cultures of hepatocytes and biliary epithelium. Experiments were designed to evaluate the influence of ethanol (EtOH), lipopolysaccharide (LPS), and acetaldehyde (ACA) on OPN and PPAR-alpha expression levels in vivo (rats and mice) and in vitro (hepatocytes and biliary epithelium). Adult Sprague-Dawley rats and C57BL6 mice were fed EtOH-containing Lieber-DeCarli liquid diet for 6 weeks and injected with a single dose of LPS. A combination of EtOH and LPS treated rats and mice showed significant induction of hepatic OPN expression compared with the controls. Similarly, cells exposed to physiological doses of EtOH, LPS, a combination of EtOH and LPS, and ACA resulted in increased OPN protein and mRNA expression. Rats and mice in ALD model and cells treated with EtOH and ACA showed downregulation of PPAR-alpha mRNA. Also, DNA binding activity of PPAR-alpha to PPAR response element was significantly reduced following treatment. Overexpression of PPAR-alpha rescued the reduced PPAR-alpha activity and PPAR-alpha agonist, bezafibrate, elevated PPAR-alpha activity after treatment of EtOH, LPS, and ACA when cells were exposed by bezafibrate. To further delineate the potential relationship between OPN and PPAR-alpha, OPN(-/-) mice showed no change of PPAR-alpha mRNA level although wild-type mice showed downregulation of PPAR-alpha mRNA after EtOH treatment. In conclusion, the current study suggests that OPN is induced by EtOH and its metabolite ACA and opposite relationship likely exist between PPAR-alpha and OPN expression within the liver during ALD.

Activation of Mouse and Human Peroxisome Proliferator−Activated Receptor Alpha by Perfluoroalkyl Acids of Different Functional Groups and Chain Lengths

Perfluoroalkyl acids (PFAAs) are surfactants used in consumer products and persist in the environment. Some PFAAs elicit adverse effects on rodent development and survival. PFAAs can activate peroxisome proliferator-activated receptor alpha (PPARalpha) and may act via PPARalpha to produce some of their effects. This study evaluated the ability of numerous PFAAs to induce mouse and human PPARalpha activity in a transiently transfected COS-1 cell assay. COS-1 cells were transfected with either a mouse or human PPARalpha receptor-luciferase reporter plasmid. After 24 h, cells were exposed to either negative controls (water or dimethyl sulfoxide, 0.1%); positive control (WY-14643, PPARalpha agonist); perfluorooctanoic acid or perfluorononanoic acid at 0.5-100 microM; perfluorobutanoic acid, perfluorohexanoic acid, perfluorohexane sulfonate, or perfluorodecanoic acid (PFDA) at 5-100 microM; or perfluorobutane sulfonate or perfluorooctane sulfonate at 1-250 microM. After 24 h of exposure, luciferase activity from the plasmid was measured. Each PFAA activated both mouse and human PPARalpha in a concentration-dependent fashion, except PFDA with human PPARalpha. Activation of PPARalpha by PFAA carboxylates was positively correlated with carbon chain length, up to C9. PPARalpha activity was higher in response to carboxylates compared to sulfonates. Activation of mouse PPARalpha was generally higher compared to that of human PPARalpha. We conclude that, in general, (1) PFAAs of increasing carbon backbone chain lengths induce increasing activity of the mouse and human PPARalpha with a few exceptions, (2) PFAA carboxylates are stronger activators of mouse and human PPARalpha than PFAA sulfonates, and (3) in most cases, the mouse PPARalpha appears to be more sensitive to PFAAs than the human PPARalpha in this model.

Peroxisome proliferator-activated receptor- reduces inflammation and vascular leakage in a murine model of acute lung injury

Acute lung injury (ALI) still represents a major cause of morbidity and mortality in intensive care units. Beneficial effects have been described after activation of the peroxisome proliferator-activated receptor (PPAR)-alpha by fibrates such as WY 14,643 (WY) in inflammatory models. In the present study, the impact of WY was investigated in a model of endotoxin (lipopolysaccharide; LPS)-induced ALI in mice. Intratracheal LPS challenge dose-dependently resulted in leukocyte invasion, protein leakage and release of tumour necrosis factor-alpha as well as macrophage inflammatory protein-2, prostaglandin E(2) and thromboxane B(2) into the alveolar space after 8 and 24 h. Lung ventilator compliance was reduced at both time-points. In isolated perfused mouse lungs, platelet-activating factor (PAF) induced an acute increase in pulmonary artery pressure (P(pa)) and in capillary filtration coefficient (K(fc)). WY significantly improved all features of ALI in vivo and blunted the increase in K(fc) in isolated perfused mice lungs. In mice with genetic deletion of PPAR-alpha, all characteristics of ALI, P(pa), and K(fc) were not significantly different from wild-type mice but WY failed to improve ALI and PAF-induced increase in K(fc). Activation of peroxisome proliferator-activated receptor-alpha by WY 14,643 reduced acute lung injury and vascular leakage. Fibrates may possess beneficial effects in acute pulmonary diseases beyond their lipid-lowering capability.

Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism

There is controversy regarding whether fructose in liquid beverages constitutes another dietary ingredient of high caloric density or introduces qualitative changes in energy metabolism that further facilitate the appearance of metabolic diseases. Central to this issue is the elucidation of the molecular mechanism responsible for the metabolic alterations induced by fructose ingestion. Fructose administration (10% wt/vol) in the drinking water of Sprague-Dawley male rats for 14 days induced hyperleptinemia and hepatic leptin resistance. This was caused by impairment of the leptin-signal transduction mediated by both janus-activated kinase-2 and the mitogen-activated protein kinase pathway. The subsequent increase in activity in the liver of the unphosphorylated and active form of the forkhead box O1 nuclear factor, which transrepresses peroxisome proliferator-activated receptor alpha activity, and a lack of activation of the adenosine monophosphate-activated protein kinase, led to hypertriglyceridemia and hepatic steatosis. These alterations are attributable to two key events: (1) an increase in the amount of suppressor of cytokine signaling-3 protein, which blocks the phosphorylation and activation of janus-activated kinase-2 and Tyr(985) on the long form of the leptin receptor; and (2) a common deficit of phosphorylation in serine/threonine residues of key proteins in leptin-signal transduction pathways. The latter is probably produced by the early activation of protein phosphatase 2A, and further sustained by the accumulation in liver tissue of ceramide, an activator of protein phosphatase 2A, due to incomplete oxidation of fatty acids. Our data indicate that fructose ingestion as a liquid solution induces qualitative changes in liver metabolism that lead to metabolic diseases.

N-3 polyunsaturated fatty acid regulation of hepatic gene transcription

The liver plays a central role in whole body lipid metabolism and adapts rapidly to changes in dietary fat composition. This adaption involves changes in the expression of genes involved in glycolysis, de-novo lipogenesis, fatty acid elongation, desaturation and oxidation. This review brings together metabolic and molecular studies that help explain n-3 (omega-3) polyunsaturated fatty acid regulation of hepatic gene transcription. Dietary n-3 polyunsaturated fatty acid regulates hepatic gene expression by targeting three major transcriptional regulatory networks: peroxisome proliferator-activated receptor alpha, sterol regulatory element binding protein-1 and the carbohydrate regulatory element binding protein/Max-like factor X heterodimer. 22:6,n-3, the most prominent n-3 polyunsaturated fatty acid in tissues, is a weak activator of peroxisome proliferator-activated receptor alpha. Hepatic metabolism of 22:6,n-3, however, generates 20:5,n-3, a strong peroxisome proliferator-activated receptor alpha activator. In contrast to peroxisome proliferator-activated receptor alpha, 22:6,n-3 is the most potent fatty acid regulator of hepatic sterol regulatory element binding protein-1. 22:6,n-3 suppresses sterol regulatory element binding protein-1 gene expression while enhancing degradation of nuclear sterol regulatory element binding protein-1 through 26S proteasome and Erk1/2-dependent mechanisms. Both n-3 and n-6 polyunsaturated fatty acid suppress carbohydrate regulatory element binding protein and Max-like factor X nuclear abundance and interfere with glucose-regulated hepatic metabolism. These studies have revealed unique mechanisms by which specific polyunsaturated fatty acids control peroxisome proliferator activated receptor alpha, sterol regulatory element binding protein-1 and carbohydrate regulatory element binding protein/Max-like factor X function. As such, specific metabolic and signal transduction pathways contribute significantly to the fatty acid regulation of these transcription factors and their corresponding regulatory networks.

An aqueous extract of Salacia oblonga root, a herb-derived peroxisome proliferator-activated receptor-alpha activator, by oral gavage over 28 days induces gender-dependent hepatic hypertrophy in rats

Activation of peroxisome proliferator-activated receptor (PPAR)-alpha by natural and synthetic chemicals induces hepatic hypertrophy. An aqueous extract of Salacia oblonga root (SOW) is an Ayurvedic medicine with anti-diabetic and anti-obesity properties. In the present study, it was found that SOW (100, 300 and 900mg/kg, once daily by oral gavage over a 28 day period) elicited dose-related increases in liver weight (LW) by 1.6%, 13.4% and 42.5%, respectively, and in the ratio of LW to body weight by 8.8%, 16.7% and 40.2%, respectively, in male rats. These effects were less pronounced in females. SOW selectively increased liver mass in male rats but Sudan red staining was not different, which indicates that hepatic lipid accumulation was similar in both genders. However, SOW even at the highest dosage did not influence serum ALT and AST activities in male or female rats. Moreover, SOW was found to activate PPAR-alpha in human hepatoma-derived HepG2 cells, as evidenced by the upregulation of PPAR-alpha and acyl-CoA oxidase mRNA expression. Thus, SOW-dependent PPAR-alpha activation may precede the development of the gender difference in hepatic hypertrophy; this process may be influenced by sex hormone status.

Therapeutic Effects of Fibrates in Postprandial Lipemia

Hypertriglyceridemia is observed in many metabolic diseases such as the metabolic syndrome, diabetes mellitus, or mixed dyslipidemia frequently leading to premature coronary heart disease (CHD). Additionally, several studies have shown that postprandial hypertriglyceridemia is pronounced in patients with CHD, metabolic syndrome, hypertension, and other pathologic conditions. The triglyceride-rich lipoprotein remnants accumulating in the postprandial state seem to be involved in atherogenesis and in events leading to thrombosis. Since abnormal postprandial lipemia is associated with pathologic conditions, its treatment is of clinical importance.Fibrates are of significant help in managing hypertriglyceridemia. This review summarizes the effect of fibric acid derivatives on postprandial lipemia. Fibrates decrease the production of and enhance the catabolism of triglyceride-rich lipoproteins through the activation of peroxisome proliferator-activated receptor-alpha. Results of clinical studies with fibrates have confirmed their action in decreasing postprandial triglyceride levels by increasing lipoprotein lipase activity, decreasing apolipoprotein CIII production, and by increasing fatty acid oxidation in the liver.It is concluded that fibrates are effective agents in lowering the postprandial increase in remnant lipoprotein particles and retinyl palmitate. Furthermore, fibrates can also affect the postprandial lipid profile by increasing hepatic lipase levels and in some cases, by reducing cholesterol ester transfer protein activity. The main target of fibrate therapy is to improve fasting hypertriglyceridemia, which is an essential component associated with improving postprandial lipemia. Fibrates are well tolerated by patients and adverse effects have been reported rarely after their administration.

Auraptene, a citrus fruit compound, regulates gene expression as a PPARα agonist in HepG2 hepatocytes

Citrus fruit compounds have various activities that improve pathological conditions in many tissues. In this study, we examined the effect of auraptene contained mainly in the peel of citrus on peroxisome proliferator-activated receptor-alpha (PPARalpha) activation. To examine effects of auraptene on the PPARalpha activation in hepatocytes, PPAR ligand assay system was developed using HepG2 hepatocytes, in which the endogenous PPARalpha expression level is very low. In the PPAR ligand assay, the addition of auraptene showed significant effects on the transactivation of GAL4/PPARalpha chimera proteins in a dose-dependent manner. Actually, treatment with auraptene induced the up-regulation of PPAR target genes, such as acyl-CoA oxidase (ACO), carnitine-palmitoyl transferase 1A (CPT1A) and acyl-CoA synthetase (ACS), in PPARalpha-expressing HepG2 hepatocytes. The regulation of gene expression was dependent on PPARalpha because mock-transfected HepG2 hepatocytes showed no regulation. The up-regulation of PPAR target gene expression by auraptene was sufficient to enhance oleic acid uptake into PPARalpha-expressing HepG2 hepatocytes. These results indicate that auraptene acts as a PPARalpha agonist in hepatocytes and that auraptene may improve lipid abnormality through PPARalpha activation in the liver.

Modulation of receptor phosphorylation contributes to activation of peroxisome proliferator activated receptor alpha by dehydroepiandrosterone and other peroxisome proliferators.

Dehydroepiandrosterone (DHEA), a C19 human adrenal steroid, activates peroxisome proliferator-activated receptor alpha (PPARalpha) in vivo but does not ligand-activate PPARalpha in transient transfection experiments. We demonstrate that DHEA regulates PPARalpha action by altering both the levels and phosphorylation status of the receptor. Human hepatoma cells (HepG2) were transiently transfected with the expression plasmid encoding PPARalpha and a plasmid containing two copies of fatty acyl coenzyme oxidase (FACO) peroxisome-proliferator activated receptor responsive element consensus oligonucleotide in a luciferase reporter gene. Nafenopin treatment increased reporter gene activity in this system, whereas DHEA treatment did not. Okadaic acid significantly decreased nafenopin-induced reporter activity in a concentration-dependent manner. Okadaic acid treatment of primary rat hepatocytes decreased both DHEA- and nafenopin-induced FACO activity in primary rat hepatocytes. DHEA induced both PPARalpha mRNA and protein levels, as well as PP2A message in primary rat hepatocytes. Western blot analysis showed that the serines at positions 12 and 21 were rapidly dephosphorylated upon treatment with DHEA and nafenopin. Results using specific protein phosphatase inhibitors suggested that protein phosphatase 2A (PP2A) is responsible for DHEA action, and protein phosphatase 1 might be involved in nafenopin induction. Mutation of serines at position 6, 12, and 21 to an uncharged alanine residue significantly increased transcriptional activity, whereas mutation to negative charged aspartate residues (mimicking receptor phosphorylation) decreased transcriptional activity. DHEA action involves induction of PPARalpha mRNA and protein levels as well as increased PPARalpha transcriptional activity through decreasing receptor phosphorylation at serines in the AF1 region.