PPARα Expression In Liver Research Articles

Pomegranate Seed Oil as a Source of Conjugated Linolenic Acid (CLnA) Has No Effect on Atherosclerosis Development but Improves Lipid Profile and Affects the Expression of Lipid Metabolism Genes in apoE/LDLR-/- Mice.

The aim of this study was to evaluate the anti-atherosclerotic effect of pomegranate seed oil as a source of conjugated linolenic acid (CLnA) (cis-9,trans-11,cis-13; punicic acid) compared to linolenic acid (LnA) and conjugated linoleic acid (CLA) (cis-9,trans-11) in apoE/LDLR-/- mice. In the LONG experiment, 10-week old mice were fed for the 18 weeks. In the SHORT experiment, 18-week old mice were fed for the 10 weeks. Diets were supplied with seed oils equivalent to an amount of 0.5% of studied fatty acids. In the SHORT experiment, plasma TCh and LDL+VLDL cholesterol levels were significantly decreased in animals fed CLnA and CLA compared to the Control. The expression of PPARα in liver was four-fold increased in CLnA group in the SHORT experiment, and as a consequence the expression of its target gene ACO was three-fold increased, whereas the liver's expression of SREBP-1 and FAS were decreased in CLnA mice only in the LONG experiment. Punicic acid and CLA isomers were determined in the adipose tissue and liver in animals receiving pomegranate seed oil. In both experiments, there were no effects on the area of atherosclerotic plaque in aortic roots. However, in the SHORT experiment, the area of atherosclerosis in the entire aorta in the CLA group compared to CLnA and LnA was significantly decreased. In conclusion, CLnA improved the lipid profile and affected the lipid metabolism gene expression, but did not have the impact on the development of atherosclerotic plaque in apoE/LDLR-/- mice.

Oleoylethanolamide Protects Against Acute Liver Injury by Regulating Nrf-2/HO-1 and NLRP3 Pathways in Mice.

Acute liver injury is a rapidly deteriorating clinical condition with markedly high morbidity and mortality. Oleoylethanolamide (OEA) is an endogenous lipid messenger with multiple bioactivities, and has therapeutic effects on various liver diseases. However, effects of OEA on acute liver injury remains unknown. In this study, effects and mechanisms of OEA in lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury in mice were investigated. We found that OEA treatment significantly attenuated LPS/D-Gal-induced hepatocytes damage, reduced liver index (liver weight/body weight), decreased plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Moreover, mechanism study suggested that OEA pretreatment significantly reduced hepatic MDA levels, increased Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) activities via up-regulate Nrf-2 and HO-1 expression to exert anti-oxidation activity. Additionally, OEA markedly reduced the expression levels of Bax, Bcl-2 and cleaved caspase-3 to suppress hepatocyte apoptosis. Meanwhile, OEA remarkedly reduced the number of activated intrahepatic macrophages, and alleviated the mRNA expression of pro-inflammatory factors, including TNF-α, IL-6, MCP1 and RANTES. Furthermore, OEA obviously reduced the expression of IL-1β in liver and plasma through inhibit protein levels of NLRP3 and caspase-1, which indicated that OEA could suppress NLRP3 inflammasome pathway. We further determined the protein expression of PPAR-α in liver and found that OEA significantly increase hepatic PPAR-α expression. In addition, HO-1 inhibitor ZnPP blocked the therapeutic effects of OEA on LPS/D-Gal-induced liver damage and oxidative stress, suggesting crucial role of Nrf-2/HO-1 pathway in the protective effects of OEA in acute liver injury. Together, these findings demonstrated that OEA protect against the LPS/D-Gal-induced acute liver injury in mice through the inhibition of apoptosis, oxidative stress and inflammation, and its mechanisms might be associated with the Nrf-2/HO-1 and NLRP3 inflammasome signaling pathways.

Aurantio-obtusin improves obesity and insulin resistance induced by high-fat diet in obese mice.

Aurantio-obtusin (AUR) is the main bioactive compound among the anthraquinones, from Cassia seed extract. This study was conducted to identify whether AUR could improve obesity and insulin resistance, induced by a high-fat diet in obese mice. Mice were fed a high-fat diet for 6 weeks and were then assigned to the high-fat diet (HFD) control group, the AUR 5 mg/kg group, or the AUR 10 mg/kg group. AUR improves glucose by activating the expression of PI3K, Akt and GLUT4, GLUT2. AUR altered the expression levels of several lipid metabolism-related and adipokine genes. AUR decreased the mRNA expression of PPAR-γ, FAS and increased the mRNA expression of PPAR-α in liver. AUR lowered SREBP-1c, FAS, SCD-1, inflammatory cytokines, and increased the expression of PPAR-γ, PPAR-α, CPT-1, and adiponectin in white adipose tissue (WAT). AUR docking with the insulin receptor showed that the residues of the insulin receptor, ectodomain, were the same as those around the emodin. The effect of AUR may be elicited by regulating the activity of the insulin signaling pathway, expression of lipid metabolism-related genes, and expression of inflammatory cytokine markers to improve adiposity, insulin resistance, and dyslipidemia.

Anti-hyperlipidemic effect of flavone-rich <i>Belamcanda chinensis</i> (L.) DC. (Iridaceae) leaf extract in ICR mice fed high-fat diet

Purpose: To assess the anti-hyperlidemic effect of flavone-rich B. chinensis leaf extract (HTP) in ICR mice fed a high-fat diet.Methods: HTP (100, 200 and 400 mg/kg) were orally administered to ICR mice fed high-fat diet for 7 weeks. Blood glucose, as well as serum and hepatic levels of lipids were determined at the end of the experiment. Phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and protein level of peroxisome proliferator-activated receptor α (PPARα) were analyzed by Western blot and enzyme-linked immunosorbent assay (ELISA) kit, respectively.Results: Treatment with HTP significantly decreased peri-epididymal fat weight (p < 0.01 and p < 0.05 for 200 and 100 mg/kg, respectively), lowered serum and hepatic lipid, and decreased glucose area under curve (AUC) in oral glucose tolerance test (p < 0.01 for 200 mg/kg). Western blot and ELISA analysis showed that administration of HTP (200 mg/kg) significantly increased AMPK (p < 0.05) phosphorylation and PPARα expression in liver (p < 0.05).Conclusion: HTP can alleviate hyperlipidemia, at least in part, by up-regulation of AMPK and PPARα.Keywords: Belamcanda chinensis, Flavone, Hyperlipidemia, Adenosine 5′-monophosphate-activated protein kinase, Peroxisome proliferator activated receptor-alpha, Glucose tolerance

Pigs fed saturated fat/cholesterol have a blunted hypothalamic-pituitary-adrenal function, are insulin resistant and have decreased expression of IRS-1, PGC1α and PPARα

The increasing incidence of insulin resistance has been linked to both increased intake of saturated fatty acids and disruption of the hypothalamic-pituitary-adrenal (HPA) axis. We tested the hypothesis that adding saturated fat/cholesterol to the diet of growing pigs would both disrupt HPA function and cause insulin resistance. Three-month-old pigs were fed either a control (13% energy from fat) or a high saturated fatty acid cholesterol (HSFC) diet (44% energy from fat; 2% cholesterol). After 10 weeks on the diets, intravenous ACTH, insulin and glucose challenges were performed, and after 12 weeks, tissue samples were taken for measurement of mRNA and for lipid-rich aortic lesions. Plasma total, HDL- and LDL-cholesterol were significantly increased in pigs fed the HSFC diet. Cortisol release during the ACTH challenge was suppressed in HSFC-fed pigs which were also more insulin resistant and glucose intolerant than controls. The HSFC diet decreased the expression of insulin receptor (IR) and insulin receptor substrate-1 in muscle and adipose tissue as well as adiponectin and adiponectin receptor 2 expression in fat. The HSFC diet decreased PGC-1α and PPARα expression in muscle but increased PPARα expression in liver. There was a trend for an increase in lipid-stained lesion frequency around the abdominal branches of the aorta in HSFC-fed pigs. We conclude that feeding increased saturated fat to pigs causes disruption in the HPA axis, insulin resistance and decreased muscle and adipose expression of genes controlling insulin signalling and mitochondrial oxidative capacity.

Decrease of Blood Lipids Induced by Shan-Zha (Fruit of Crataegus pinnatifida) is Mainly Related to an Increase of PPARα in Liver of Mice Fed High-Fat Diet

Hyperlipidemia is an important risk factor for cardiovascular diseases. Agents for the treatment of hyperlipidemia are well-developed in the clinic while PPARα is a target for lipid-lowering agents. Shan-Zha (Crataegus pinnatifida) is a traditional Chinese medicine used to increase digestion. Also, Shan-Zha fruit extract showed merit to improve obesity and hyperlipidemia in hamsters; however, the mechanism remained obscure. In the present study, hypertriglycemia and hypercholesterolemia were induced by high fat diet in C57BL/6 J male mice. Then, they were orally administered with Shan-Zha fruit extract at an effective dose of 250 mg/kg for 7 days. The liver was removed to estimate the expressions of PPARα and β-oxidation-related enzyme. Oral intake of Shan-Zha extract significantly improved hyperlipidemia in high fat diet-fed mice with an increase of PPARα expression in liver. Also, expression of PPARα-regulated β-oxidation-related enzymes was raised in liver by Shan-Zha extract. However, adipose tissue and others were not modified by this treatment of Shan-Zha fruit extract. Thus, Shan-Zha can increase the expression of PPARα to facilitate β-oxidation-related enzymes in liver for lipid degradation and blood lipid decrement. Also, this is the first report showing Shan-Zha fruit extract can influence liver to lower hyperlipidemia prior to the action in adipose tissue.

Effects of soybean isoflavone on liver lipid metabolism in nonalcoholic fatty liver rats

To study the effects of soybean isoflavone on liver lipid, serum lipid, antioxidant index and hepatic lipid metabolism associated factors in nonalcoholic fatty liver rats. Thirty-six male rats (SD) were randomly divided into four groups by weight: normal control group, nonalcoholic fatty liver disease (NAFLD) model control group, low-dose isoflavone treatment group (10 mg/kg) and high-dose isoflavone group (20 mg/kg), 9 rats in each group. Normal control rats were fed with D12450B (10% fat energy), model control and isoflavone intervention rats were fed with D12492 (60% fat energy). Twelve weeks later, liver lipid, serum lipid and antioxidant index were observed. Liver sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS) and peroxisome proliferators activated receptor alpha (PPAR alpha) were detected by western blotting. Liver triglyceride (TG) in normal control group, NAFLD model control group, low-dose isoflavone group and high-dose isoflavone group were (8.11 ± 4.13), (57.06 ± 16.95), (31.26 ± 10.48), (31.38 ± 13.25) mmol/mg protein, respectively (F = 22.569, P < 0.01); liver free fatty acid (FFA) were (0.030 ± 0.007), (0.042 ± 0.009), (0.038 ± 0.009), (0.032 ± 0.005) µmol/mg protein, respectively (F = 4.857, P < 0.01); liver superoxide dismutase (SOD) activity were (502.29 ± 23.71), (201.83 ± 16.99), (228.93 ± 21.71), (238.08 ± 15.96) U/mg protein, respectively (F = 9.555, P < 0.01); liver malondialdehyde (MDA) were (1.29 ± 0.29), (2.85 ± 0.73), (2.07 ± 0.49), (2.03 ± 0.37) nmol/mg protein, respectively (F = 13.449, P < 0.01); SREBP-1c protein expression were 0.45 ± 0.16, 1.42 ± 0.30, 1.02 ± 0.31, 0.47 ± 0.27, respectively (F = 24.515, P < 0.01); FAS protein expression were 0.27 ± 0.08, 1.97 ± 0.47, 1.35 ± 0.30, 0.49 ± 0.12, respectively (F = 60.361, P < 0.01); PPARα protein expression were 2.03 ± 0.56, 0.41 ± 0.17, 0.81 ± 0.27, 0.66 ± 0.16, respectively (F = 37.97, P < 0.01). Soy isoflavone can reduce the hepatic lipid deposition and increase antioxidant capacity, the mechanism may be related to inhibition of SREBP-1c and activation of PPARα expression in liver.

Evidence for a new human CYP1A1 regulation pathway involving PPAR-α and 2 PPRE sites

Cytochrome P450 1A1 catalyzes the degradation of endobiotics (estradiol, fatty acids, and so on) and the bioactivation of numerous environmental procarcinogens, such as arylamines and polycyclic aromatic hydrocarbons, that are found in food. Several peroxisome proliferators and arachidonic acid derivatives enhance cytochrome P450 1A1 activity, but the mechanisms involved remain unknown. The aim of this work was to study the role of peroxisome proliferator-activated receptors in cytochrome P450 1A1 gene induction. The role of peroxisome proliferator-activated receptor transcription factors in cytochrome P450 1A1 induction was assessed by means of enzymatic activities, quantitative real-time polymerase chain reaction, gene reporter assays, mutagenesis, and electrophoretic mobility shift assay. We show that peroxisome proliferator-activated receptor-alpha agonists (WY-14643, bezafibrate, clofibrate, and phthalate) induce human cytochrome P450 1A1 gene expression, whereas 2,4-thiazolidinedione, a specific peroxisome proliferator-activated receptor-gamma agonist, represses it. The induction of cytochrome P450 1A1 transcripts by WY-14643 was associated with a marked increase of ethoxyresorufin O -deethylase activity (10-fold at 200 mumol/L). Transfection of peroxisome proliferator-activated receptor-alpha complementary DNA enhanced cytochrome P450 1A1 messenger RNA induction by WY-14643, although WY-14643 failed to activate xenobiotic responsive element sequences. Two peroxisome proliferator response element sites were located at positions -931/-919 and -531/-519 of the cytochrome P450 1A1 promoter. Their inactivation by directed mutagenesis suppressed the inductive effect of WY-14643 on cytochrome P450 1A1 promoter activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay experiments showed that the 2 cytochrome P450 1A1 peroxisome proliferator response element sites bind the peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha heterodimer. We describe here a new cytochrome P450 1A1 induction pathway involving peroxisome proliferator-activated receptor-alpha and 2 peroxisome proliferator response element sites, indicating that peroxisome proliferator-activated receptor-alpha ligands, which are common environmental compounds, may be involved in carcinogenesis.

Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator–activated receptors in the liver and adipose tissue of the offspring

The effect of protein consumption during pregnancy on peroxisomal proliferator-activated receptor (PPAR) expression and plasma lipid concentrations in the offspring were determined in the rat. Rats were fed isocaloric diets containing either 18% (w/w) (control) or 9% (w/w) casein throughout pregnancy, and chow during lactation. Maternal protein intake did not alter fetal hepatic PPARα and γ expression at 20/21 days gestation ( n = 5/group). Liver PPARα expression was 69% greater ( P < 0.0001) in the 9% group, whereas PPARγ was not altered, in the offspring 6 days after weaning ( n = 5/group). Adipose PPARγ expression was 59% lower ( P < 0.01) in the 9% group after weaning. This was accompanied by an increase (35%, P < 0.02) in plasma triacylglycerol and nonesterified fatty acid concentrations (55%, ( P < 0.01) in the 9% group after weaning. These data show that maternal protein intake during pregnancy alters the regulation of PPAR expression, which represents a potential mechanism to explain impaired lipid homeostasis in the offspring.

Sexual dimorphism in lipid metabolic phenotype associated with old age in Sprague–Dawley rats

Purpose. Aged male rats show a decrease in liver PPARα. We aimed to determine if the sexual dimorphism in lipid metabolism observed in the PPARα −/− mouse is also present in senescent rats. Results. Eighteen-month old rats were obese and presented high plasma NEFA concentrations. Old male rats were more hypercholesterolemic and hyperleptinemic than females, presenting a higher content in hepatic triglycerides and cholesteryl esters, while 18-month old females were more hypertriglyceridemic than males. Although PPARα expression and binding activity was reduced in liver from old male and female rats, the mRNA for a PPARα target gene, such as CPT-I, was reduced in old males (−56%), while increased by 286% in old females. LXRα protein was increased, and its binding activity was decreased in livers of old males, while livers of old females showed an increase in DGAT1 (2.6-fold) and DGAT2 (4.9-fold) mRNA, with respect to 3-month old animals. The increases in DGAT1 and DGAT2 mRNAs matched in old females those of plasma (3.1-fold) and liver triglycerides (5.0-fold). Conclusions. These features disclose a marked sexual dimorphism in lipid metabolism associated to old age in rats that can be partially attributed not only to an age-related decrease in liver PPARα expression, but also to changes in other hepatic transcription factors and enzymes, such as liver X receptor alpha (LXRα) and diacylglycerol acyltransferases (DGAT).

Chronic leptin administration increases serum NEFA in the pig and differentially regulates PPAR expression in adipose tissue

Two in vivo studies were conducted with pigs to determine the effects of exogenous leptin on the expression of peroxisome proliferator activated receptors (PPAR), and on serum concentrations of selected metabolites and hormones. Initially, leptin was administered i.m. to young pigs for 15 days at 0 (control), 0.003 (low), 0.01 (medium) and 0.03 (high) mg · kg -1 · day -1. There was no leptin effect on serum glucose ( P > 0.84), triglycerides ( P > 0.69), non-esterified fatty acids (NEFA, P > 0.53), or glycerol ( P > 0.33). Leptin at the intermediate and high doses depressed adipose expression of both PPARγ1 ( P < 0.06) and PPARγ2 ( P < 0.01). In a second study, we used a paired-feeding experimental design to determine the effects of a higher dose of leptin (0.05 mg · kg -1 · day -1) on serum metabolites and PPAR expression in selected tissues. At this dose, leptin increased ( P < 0 .0001) serum NEFA concentrations relative to both the ad libitum and pair-fed control groups. However, in this study, there was no difference in the expression of PPARγ1 in adipose tissue, but PPARγ2 mRNA was upregulated by leptin ( P < 0.08). In contrast, leptin had no impact on the expression of PPARα in liver, skeletal muscle or adipose tissue. Adipose tissue explants were also incubated with leptin to assess the effect on PPARγ expression, in vitro. The abundance of PPARγ1 mRNA ( P < 0.05) was increased after 24 hr of exposure, but the effect of leptin on γ2 was not significant ( P > 0.24). The lipolytic effect of leptin was also evaluated in vitro using isolated adipocytes. In keeping with the increase in serum NEFA concentrations in vivo, leptin stimulated lipolysis in vitro, increasing glycerol concentrations in the medium to about 219% of that in basal (non-treated) culture medium after 8 hr of incubation. Collectively, the data presented herein indicate that leptin modulates lipid metabolism in the pig, but that PPARα expression is not a parallel target of leptin as it is in rodent models. The regulation of PPARγ by leptin seems complex in that it varied in relation to dose in vivo, and may be impacted by in vitro vs. in vivo circumstances.