http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031317Potent PPARα Activator Derived from Tomato Juice, 13-oxo-9,11-Octadecadienoic Acid, Decreases Plasma and Hepatic Triglyceride in Obese Diabetic MiceDyslipidemia is a major risk factor for development of several obesity-related diseases. The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates energy metabolism. Previously, we reported that 9-oxo-10,12-octadecadienoic acid (9-oxo-ODA) is presented in fresh tomato fruits and acts as a PPARα agonist. In addition to 9-oxo-ODA, we developed that 13-oxo-9,11-octadecadienoic acid (13-oxo-ODA), which is an isomer of 9-oxo-ODA, is present only in tomato juice. In this study, we explored the possibility that 13-oxo-ODA acts as a PPARα agonist in vitro and whether its effect ameliorates dyslipidemia and hepatic steatosis in vivo. In vitro luciferase assay experiments revealed that 13-oxo-ODA significantly induced PPARα activation; moreover, the luciferase activity of 13-oxo-ODA was stronger than that of 9-oxo-ODA and conjugated linoleic acid (CLA), which is a precursor of 13-oxo-ODA and is well-known as a potent PPARα activator. In addition to in vitro experiment, treatment with 13-oxo-ODA decreased the levels of plasma and hepatic triglycerides in obese KK-Ay mice fed a high-fat diet. In conclusion, our findings indicate that 13-oxo-ODA act as a potent PPARα agonist, suggesting a possibility to improve obesity-induced dyslipidemia and hepatic steatosis.
Introduction Top
Obesity is a major risk factor for chronic diseases including diabetes, cardiovascular diseases, and hypertension [1]–[4]. Dyslipidemia, in particular, is a direct risk factor for arteriosclerosis, and for liver cirrhosis, and may be partially due to the dysfunction of lipid metabolism in the liver. Therefore, to prevent or reduce arteriosclerosis and cirrhosis, it is important to ameliorate the dysfunction of hepatic lipid metabolism dysfunction.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily, which regulate energy homeostasis (glucose and lipid metabolisms), inflammation, proliferation, and differentiation [5]–[9]. In particular, PPARα acts as a master regulator of fatty acid oxidation by controlling the transcription of its target genes [10], [11]. Consistent with this function, PPARα is mainly expressed in tissues with high lipid catabolic capacities, such as the liver, skeletal muscle, and brown adipose tissue [7], [12]. It has been reported that the activation of PPARα enhances fatty acid oxidation in the liver and decreases the levels of circulating and cellular lipids in obese diabetic patients [9], [13]. Therefore, the regulation of PPARα activity is one of the most important means of managing chronic disease related to dysfunction in lipid metabolism in the liver.
During the past decade, numerous studies have shown that endogenous and naturally occurring biological molecules, including fatty acids and fatty acid-derivatives, serve as PPARα agonists [14], [15]. In particular, conjugated linoleic acid (CLA) is well known as a potent PPARα agonist [16] and treatment with CLA actually increases the catabolism of lipids in the liver in rodents [17]. However, the effects of CLA derivatives on PPARα remain unclear.
Recently, we reported that a particular CLA derivative, 9-oxo-10,12-octadecadienoic acid (9-oxo-ODA), is present in fresh tomato fruit, and serves as a PPARα agonist [18]. In mouse primary hepatocytes, 9-oxo-ODA enhanced fatty acid oxidation via PPARα activation and consequently inhibited triglyceride accumulation [18]. Interestingly, we developed that processed products such as tomato juice contain 13-oxo-9,11-octadecadenoic acid (13-oxo-ODA), an isomer of 9-oxo-ODA, which was not present in fresh tomato fruit [19].
In this study, we explored whether 13-oxo-ODA acts as a PPARα agonist in vitro and ameliorates dyslipidemia and hepatic steatosis in vivo. Treatment with 13-oxo-ODA activated PPARα in mouse primary hepatocytes. Furthermore, treatment of obese diabetic KK-Ay mice with 13-oxo-ODA suppressed the increase in plasma and hepatic triglyceride (TG) levels resulting from a high-fat diet (HFD), through PPARα activation in peripheral tissues such as the liver and skeletal muscle. In addition, 13-oxo-ODA treatment decreased the plasma glucose level and increased glucose the tolerance ability in the 13-oxo-ODA-fed mice, as has been shown for other PPARα agonists. These findings indicate that 13-oxo-ODA has a possibility to improve the disorder of lipid and carbohydrate metabolism, via PPARα activation.
Materials and Methods Top
Plant materials and chemicals
