Overexpression of peroxisome proliferator‐activated receptor γ and retinoid X receptor α in gastric carcinomatous tissue

OBJECTIVE: To investigate the expression of peroxisome proliferator‐activated receptor γ (PPAR‐γ) and retinoid X receptor α (RXR‐α) in chronic gastritis, gastric mucosal dysplasia and gastric carcinoma and to identify any correlations between PPAR‐γ and RXR‐α expression in this progression sequence. METHODS: Immunohistochemical methods (avidin? biotin?peroxidase complex) were used to examine the expression of PPAR‐γ and RXR‐α in 53 patients with gastric carcinoma, 18 with gastric mucosal dysplasia and 30 with chronic atrophic gastritis. Thirty‐one patients with chronic non‐atrophic gastritis acted as controls. RESULTS: The positive rates of PPAR‐γ and RXR‐α in gastric carcinoma were 41.5 and 54.7%, 27.8 and 38.9% in gastric mucosal dysplasia, 10.0 and 20.0% in chronic atrophic gastritis, and 6.5 and 16.1% in chronic non‐atrophic gastritis, respectively. The expression of PPAR‐γ and RXR‐α increased during the progression from chronic non‐atrophic gastritis to chronic atrophic gastritis, then to gastric carcinoma. Compared with chronic gastritis, the expression of PPAR‐γ and RXR‐α in gastric mucosal dysplasia and gastric carcinoma was significantly increased (P < 0.05, P < 0.01). In gastric carcinoma, the expression of PPAR‐γ and RXR‐α was not associated with tumor cell differentiation or metastasis in the lymph nodes (P > 0.05). There was a positive correlation between the expression of PPAR‐γ and RXR‐α in gastric carcinoma (r= 0.54, P < 0.01). CONCLUSIONS: Overexpression of PPAR‐γ and RXR‐α protein is apparent in human gastric cancer. This might be an early event in carcinogenesis, and both PPAR‐γ and RXR‐α may play independent and/or synergistic roles in the progression of gastric carcinoma.     

Thiazolidinedione‐independent activation of peroxisome proliferator‐activated receptor γ is a potential target for diabetic macrovascular complications

Macrovascular complications are responsible for the high morbidity and mortality in patients with diabetes. Peroxisome proliferator‐activated receptor γ (PPARγ) plays a central role in the process of adipocyte differentiation and insulin sensitization, and also possesses anti‐atherogenic effects. Recently, some statins, angiotensin II type 1 receptor blockers and calcium channel blockers have been reported to activate PPARγ. However, the impact of PPARγ activation on diabetic macrovascular complications is not fully understood. It has been reported that the activation of PPARγ by thiazolidinediones induces anti‐atherogenic effects in vascular cells, including monocytes/macrophages, endothelial cells and smooth muscle cells, in atherosclerotic animal models and in clinical studies. We have reported that hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), which are used for treatment of hypercholesterolemia, activate PPARγ and mediate anti‐atherogenic effects through PPARγ activation in macrophages. Also, telmisartan, an angiotensin type I receptor blocker, has been reported to have anti‐atherogenic effects through PPARγ activation. Furthermore, we have reported that nifedipine, a dihydropyridine calcium channel blocker, can activate PPARγ, thereby mediating anti‐atherogenic effects in macrophages. Therefore, statin therapy and part of anti‐hypertensive therapy might produce beneficial effects through PPARγ activation in hypercholesterolemic and/or hypertensive patients with diabetes, and PPARγ might be a therapeutic target for diabetic macrovascular complications. In the present review, we focus on the anti‐atherogenic effects of PPARγ and suggest potential therapeutic approaches to prevent diabetic macrovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00182.x, 2012)     

Effect of peroxisome proliferator‐activated receptors‐γ and co‐activator‐1α genetic polymorphisms on plasma adiponectin levels and susceptibility of non‐alcoholic fatty liver disease in Chinese people

Background/Aims: Peroxisome proliferator‐activated receptors‐γ (PPAR‐γ) and its co‐activator‐1α (PGC‐1α) are involved in the regulation of lipid and glucose metabolisms. This study aimed to investigate the genetic polymorphisms of PPAR‐γ and PGC‐1α in Chinese people and their influence on plasma adiponectin levels and non‐alcoholic fatty liver disease (NAFLD) susceptibility. Methods: Ninety‐six patients with NAFLD and 96 healthy controls were included. The single nucleotide polymorphisms (SNPs) of C161T PPAR‐γand Gly482Ser PGC‐1α genes were analysed by polymerase chain reaction and restriction fragment length polymorphism. Result: The CC, CT and TT genotypic distributions of the NAFLD group were significantly different from those of controls (55.2, 39.6, 5.2 vs. 74.0, 25.0, 1.0%; P=0.015). The allelic frequencies of C and T were also different between the two groups (P=0.004). As for the PGC‐1α gene, there was no difference of the genotypic and allelic frequencies between the two groups (P>0.05). In NAFLD patients, the plasma adiponectin concentrations were lower in the PPAR‐γ CT/TT genotypes compared with those in the CC genotype group (3.0±0.6 vs. 4.3±0.9, P=0.02). Multivariate logistic regression analysis showed that CT/TT genotypes of PPAR‐γ, TG, waist hip ratio, hypoadiponectinaemia and homoeostasis model assessment (HOMA)‐IR were the risk factors for NAFLD. Conclusion: SNPs in the PPAR‐γ, but not PGC‐1α, gene are associated with NAFLD susceptibility possibly through the adiponectin pathway.     

Aleglitazar,a dual peroxisome proliferator‐activated receptor‐α/γ agonist,improves insulin sensitivity,glucose control and lipid levels in people with type 2 diabetes: findings from a randomized,double‐blind trial

The present single‐centre, randomized, double‐blind, placebo‐controlled phase II study investigated the effect of the balanced dual peroxisome proliferator‐activated receptor‐α/γ agonist aleglitazar on whole‐body and liver insulin sensitivity, β‐cell function and other components of cardiometabolic syndrome after 16 weeks of treatment in patients with type 2 diabetes inadequately controlled with metformin monotherapy who received once‐daily 150 µg aleglitazar or matching placebo as add‐on therapy to metformin. Baseline and 16‐week assessments included a two‐step hyperinsulinaemic–euglycaemic clamp, followed by a hyperglycaemic clamp, as well as evaluation of glycated haemoglobin (HbA1c), lipids and safety variables. The primary endpoint was change in whole‐body insulin sensitivity (M‐value) from baseline compared with placebo, derived from the second clamp step. M‐value improved significantly from baseline with aleglitazar (n = 16) compared with placebo (n = 24; p = 0.05 for difference between arms). We found statistically significant treatment differences with aleglitazar versus placebo in fasting hepatic insulin resistance index (p = 0.01), and in total glucose disposal (p = 0.03) at the second insulin infusion step. Aleglitazar treatment resulted in significant improvements in HbA1c and lipids and was well tolerated.     

Peroxisome proliferator‐activated receptor α ligands and modulators from dietary compounds: Types,screening methods and functions

Peroxisome proliferator‐activated receptor α (PPARα) plays a key role in lipid metabolism and glucose homeostasis and a crucial role in the prevention and treatment of metabolic diseases. Natural dietary compounds, including nutrients and phytochemicals, are PPARα ligands or modulators. High‐throughput screening assays have been developed to screen for PPARα ligands and modulators in our diet. In the present review, we discuss recent advances in our knowledge of PPARα, including its structure, function, and ligand and modulator screening assays, and summarize the different types of dietary PPARα ligands and modulators.