Effect of AMPK pathway on apoptosis of human thyroid papillary cancer B-CPAP cells under low glucose and hypoxia conditions through CPT1c regulated by PPARα / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the mechanisms of carnitine palmitoyltransferase 1c (CPT1c) expression to affect the proliferation and apoptosis of human thyroid papillary cancer B-CPAP cells through the AMP-dependent/activated protein kinase (AMPK) pathway in the low glucose and hypoxic conditions. Methods: Firstly,humanthyroidpapillarycarcinomaB-CPAP cells were cultured under normal condition or low glucose and hypoxic condition respectively, followed with the treatment of AMPK inhibitor compound C. Western blotting was used to detect the expressions of AMPK, p-AMPK, peroxisome proliferator-activated receptor α (PPARα) and CPT1c; the proliferation and apoptosis were detected by CCK-8 and Flow cytometry, respectively. Then PPARα-siRNA was synthesized and transfected into B-CPAP cells to knock down PPARα, and then the cells were cultured under normal or low glucose and hypoxic condition respectively.Above indicators were also detected to verify the regulation of PPARα on CPT1c. Finally, the human luciferase reporter plasmid containing CPT1c gene promoter was constructed, and the effect of PPARα on the activity of CPT1c promoter luciferase activity was observed by immunofluorescence. Results: The expressions ofAMPK, p-AMPK, PPARα and CPT1c were significantly increased in B-CPAP cells under low glucose and hypoxia condition (P<0.05 or P<0.01), while cell proliferation and apoptosis rate did not change significantly (P>0.05). After the treatment of AMPK inhibitor compound C, the expressions of p-AMPK, PPARα and CPT1c in low glucose and hypoxia group were significantly decreased (P<0.05 or P<0.01), the inhibitory rate on cell proliferation and apoptosis rate were significantly increased (P<0.05). However, the change range was smaller than that in the normal culture + compound C group (P<0.05).After PPARα knockdown, the expressions ofAMPK, p-AMPK, PPARα and CPT1c in cancer cells cultured under normal conditions were significantly decreased (P<0.05 or P<0.01), and the inhibitory rate on cell proliferation and apoptosis rate were significantly increased (P<0.05). While under low glucose and hypoxia condition, the expression of CPT1c in cells after transfection was significantly decreased (P<0.05), and the inhibition rate on cell proliferation and the apoptosis rate were significantly increased (P<0.05); However, the change range was still lower than that of normal condition group after transfection (P<0.05).After PPARα overexpression, the ratio of fluorescence in the empty vector group was not significantly different from that of the blank group (P>0.05), and the ratio of fluorescence was significantly increased in PPARα over-expression group (P<0.05). Conclusions: AMPK can increase the expression of PPARα to promote the expression of CPT1c in thyroid cancer B-CPAP cells under low glucose and hypoxia conditions, thereby inhibiting cell apoptosis and maintaining cell proliferation ability.

Protective Effects of Ecklonia stolonifera Extract on Ethanol-Induced Fatty Liver in Rats

Chronic alcohol consumption causes alcoholic liver disease, which is associated with the initiation of dysregulated lipid metabolism. Recent evidences suggest that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver disease. Ecklonia stolonifera (ES), a perennial brown marine alga that belongs to the family Laminariaceae, is rich in phlorotannins. Many studies have indicated that ES has extensive pharmacological effects, such as antioxidative, hepatoprotective, and antiinflammatory effects. However, only a few studies have investigated the protective effect of ES in alcoholic fatty liver. Male Sprague-Dawley rats were randomly divided into normal diet (ND) (fed a normal diet for 10 weeks) and ethanol diet (ED) groups. Rats in the ED group were fed a Lieber-DeCarli liquid diet (containing 5% ethanol) for 10 weeks and administered ES extract (50, 100, or 200 mg/kg/day), silymarin (100 mg/kg/day), or no treatment for 4 weeks. Each treatment group comprised of eight rats. The supplementation with ES resulted in decreased serum levels of triglycerides (TGs), total cholesterol, alanine aminotransferase, and aspartate aminotransferase. In addition, there were decreases in hepatic lipid and malondialdehyde levels. Changes in liver histology, as analyzed by Oil Red O staining, showed that the ES treatment suppressed adipogenesis. In addition, the ES treatment increased the expression of fatty acid oxidation-related genes (e.g., PPAR-α and CPT-1) but decreased the expression of SREBP 1, which is a TG synthesis-related gene. These results suggest that ES extract may be useful in preventing fatty acid oxidation and reducing lipogenesis in ethanol-induced fatty liver.

The Effects of Peroxisome Proliferator Activated Receptor alpha (PPARalpha) Activator on Patients with Facial Erythema / 대한피부과학회지

BACKGROUND: Long-term use of topical steroids for inflammatory skin diseases can induce complications, and efforts to find a better treatment are being continued. Peroxisome proliferator activated receptor alpha (PPARalpha) suppresses the skin's inflammatory reaction, maintains the homeostasis of the skin, and plays an important role in skin barrier function. OBJECTIVE: This study analyzed the effects of a skin moisturizer containing PPARalpha activator on various inflammatory skin diseases causing facial erythema and evaluated the observed improvements. METHODS: The PPARa activator used for this study is composed of supercritical extracts from Euryale ferox, Euphorbia lathyris, and Rosa multiflora, which showed significant effects in the transactivation assay compared to Wy14643. Moisturizer containing PPARalpha was applied to the faces of 31 patients with symmetric facial erythema, with PPARalpha applied on one-half of the face and a control moisturizer on the other half of the face twice a day for 2 weeks. The percentage of erythema index, erythema index, skin hydration, and transepidermal water loss was checked to evaluate treatment effect. Both patients and clinicians each assessed the improvement of erythema on both sides of a patient's face. RESULTS: Moisturizer containing PPARalpha agonist significantly improved erythema index measured with Mexameter MX18(R) and percentage of erythema index by polarization color imaging system (DermaVision-PRO(R)) (p<0.05). However, there was no significant improvement in skin hydration and transepidermal water loss. Improvement of erythema was also shown on both the patient and clinician graded assessments. CONCLUSION: Topical PPARalpha agonist applied during clinical practice was relatively safe and effective. This can be applied clinically to various inflammatory skin diseases causing erythema.

Fenofibrato (agonista do receptor ativador da proliferação peroxissomal) modula o sistema renina-angiotensina no coração de camundongos alimentados com dieta hiperlipídica / Fenofibrate (peroxisome proliferator-activated receptor alpha agonist) modulates the renin-angiotensin system in the heart of mice fed with a high-fat diet

O objetivo deste trabalho foi estudar a ação do fenofibrato, um agonista do receptor ativador da proliferação peroxissomal alfa, no remodelamento cardíaco e na expressão de componentes do sistema renina-angiotensina (SRA) em um modelo de obesidade induzida por dieta. Camundongos machos C57B1/6 com três meses de idade foram alimentados durante 11 semanas com dieta controle (grupo C, 3,57 kcal/g de dieta) ou dieta hiperlipídica (grupo HL, 5,40 kcal/g de dieta), em seguida foram separados em quatro grupos e estudados durante cinco semanas: C; HO; C-L (C mais fenofibrato) e HL-F (HL mais fenofibrato). Os animais HL foram mais pesados e apresentaram maior pressão arterial (PA) comparados aos animais C, mas HL-F foram mais leves e tiveram PA menor que HL. A resistência insulínica vista nos camundongos HL foi melhorada com fenofibrato nos camundongos HL-F. Fenofibrato reduziu colesterol total, triglicerídeos e aumentou HDL-c. Os animais HL apresentou um ventrículo esquerdo (VE) mais pesado e com espessura da parede maior, como também cardiomiócitos maiores e uma menor razão cardiomiócito/capilares que os animais C. Fenofibrato foi eficiente em melhorar estas alterações. As expressões cardíacas de Angiotensina II (ANG II) e de seu receptor tipo 1 (AT1R) foram maiores, enquanto que a expressão de seu receptor tipo 2 (AT2R) foi menor nos animais HL que nos animais C, e fenofibrato foi eficiente em atenuar estas diferenças. Como conclusão, a dieta HL lidera para a obesidade, elevação da PA, hipertrofia cardíaca, alterações metabólicas e expressão proteica alterada do SRA em camundongos, sugerindo a participação do SRA nestas alterações. Fenofibrato é eficiente em diminuir a PA e controlar a expressão proteica do SRA, assim como no tratamento da resistência insulínica e do remodelamento cardíaco adverso, diminuindo a hipertrofia dos cardiomiócitos e melhorando a vascularização do miocárdio, desta maneira, diminuindo importantes fatores de risco para doenças ...

The aim was to study the action of fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, in cardiac remodeling and protein expressions of RAS components in a model of obesity induced by diet. 3-mo-old C57B1/6 male were fed for 11 weeks with standard chow (SC group, 3.57 kcal/g of chow) or high-fat chow (HF group, 5.40 kcal/g of chow), then they were separated into four groups and studied for five weeks: SC; HF; SC-F (SC plus fenofibrate) and HF-F (HF plus fenofibrate). HF was heavier and had higher blood pressure (BP) than SC, but HF-F was lighter and had lower BP than HF. The insulin resistance seen in HF mice was corrected by fenofibrate in HF-F mice. Fenofibrate reduced total cholesterol, triglycerides and raised the HDL-c. HF had thicker and heavier left ventricle (LV) with bigger LV cardiomyocyte and smaller cardiomyocyte-to-capillaries ratio than SC, and fenofibrate was efficient in treating these alterations. Cardiac expressions of angiotensin II (ANG II) and ANG II receptor 1 were higher, and ANG II receptor 2 was lower in HF than in SC, and fenofibrate was efficient in attenuating these differences. In conclusion , HF diet leads to obesity, BP elevation, cardiac hypertrophy, metabolic changes and altered RAS protein expression in mice, suggesting that RAS is involved. Fenofibrate is efficient in decreasing BP and in controlling RAS protein expressions, and treats the insulin resistance and the adverse cardiac remodeling decreasing the cardiomyocyte hypertrophy and improving the myocardial vascularization, therefore, decreasing important cardiovascular risk factors

Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARalpha in high fat diet-induced obese mice

Peroxisome proliferator-activated receptor alpha (PPARalpha) activation in rodents is thought to improve insulin sensitivity by decreasing ectopic lipids in non-adipose tissues. Fenofibrate, a lipid-modifying agent that acts as a PPARalpha agonist, may prevent adipocyte hypertrophy and insulin resistance by increasing intracellular lipolysis from adipose tissue. Consistent with this hypothesis, fenofibrate decreased visceral fat mass and adipocyte size in high fat diet-fed obese mice, and concomitantly increased the expression of PPARalpha target genes involved in fatty acid beta-oxidation in both epididymal adipose tissue and differentiated 3T3-L1 adipocytes. However, mRNA levels of adipose marker genes, such as leptin and TNFalpha, were decreased in epididymal adipose tissue by fenofibrate treatment. Fenofibrate not only reduced circulating levels of free fatty acids and triglycerides, but also normalized hyperinsulinemia and hyperglycemia in obese mice. Blood glucose levels of fenofibrate-treated mice were significantly reduced during intraperitoneal glucose tolerance test compared with obese controls. These results suggest that fenofibrate-induced fatty acid beta-oxidation in visceral adipose tissue may be one of the major factors leading to decreased adipocyte size and improved insulin sensitivity.

Safety and Efficacy of Peroxisome Proliferator-Activated Receptor-alpha Agonist for Treating Cardiovascular Disease

Peroxisome proliferator-activated receptor (PPAR)-alpha belongs to the nuclear family of ligand-activated transcriptional factors. The main role of PPAR-alpha is to activate the expression of the genes that are involved in fatty acid oxidation to achieve energy homeostasis. Fibrates are a known class of PPAR-alpha agonists, and they been used clinically for their effects of lowering triglycerides and elevating high-density lipoprotein-cholesterol (HDL-C). Further, recent experimental studies have demonstrated the anti-inflammatory and anti-atherosclerotic actions of PPAR-alpha agonists directly on the vascular wall. PPAR agonists are currently emerging as a promising therapeutic option to control systemic and vascular atherogenic factors. Regardless of their strong anti-atherosclerotic properties, large clinical studies have demonstrated inconsistent results for the cardioprotective effect of PPAR-alpha agonists; moreover, it has been observed that they did not decrease the total mortality, which stands in contrast to the statin trials. This review summarizes the current knowledge regarding the PPAR biology and the mechanisms of the effects of PPAR-alpha on lipid metabolism, the vessel wall and the cardiac metabolism. We also describe the results and lessons learned from the important clinical trials of PPAR-alpha agonists and we discuss these drugs' efficacy and safety.