Rice Koji Extract Enhances Lipid Metabolism through Proliferator-Activated Receptor Alpha (PPARα) Activation in Mouse Liver.

Koji is made from grains fermented with Aspergillus oryzae and is essential for the production of many traditional Japanese foods. Many previous studies have shown that koji contributes to the improvement of dyslipidemia. However, little is known regarding the underlying mechanism of this effect. Furthermore, the compound contributing to the activation of lipid metabolism is unknown. We demonstrated that rice koji extract (RKE) induces the mRNA expression of peroxisome proliferator-activated receptor alpha (PPARα) target genes, which promotes lipid metabolism in murine hepatocytes. This effect was not observed in PPARα-KO hepatocytes. We also demonstrated that RKE contained linolenic acid (LIA), oleic acid (OA), and hydroxyoctadecadienoic acids (HODEs), which activate PPARα, using LC-MS analysis. Our findings suggest that RKE, containing LIA, OA, and HODEs, could be valuable in improving dyslipidemia via PPARα activation.

9-Oxo-10(E),12(Z),15(Z)-Octadecatrienoic Acid Activates Peroxisome Proliferator-Activated Receptor α in Hepatocytes.

The peroxisome proliferator-activated receptor (PPAR)α is mainly expressed in the liver and plays an important role in the regulation of lipid metabolism. It has been reported that PPARα activation enhances fatty acid oxidation and reduces fat storage. Therefore, PPARα agonists are used to treat dyslipidemia. In the present study, we found that 9-oxo-10(E),12(Z),15(Z)-octadecatrienoic acid (9-oxo-OTA), which is a α-linolenic acid (ALA) derivative, is present in tomato (Solanum lycopersicum) extract. We showed that 9-oxo-OTA activated PPARα and induced the mRNA expression of PPARα target genes in murine primary hepatocytes. These effects promoted fatty acid uptake and the secretion of ß-hydroxybutyrate, which is one of the endogenous ketone bodies. We also demonstrated that these effects of 9-oxo-OTA were not observed in PPARα-knockout (KO) primary hepatocytes. To our knowledge, this is the first study to report that 9-oxo-OTA promotes fatty acid metabolism via PPARα activation and discuss its potential as a valuable food-derived compound for use in the management of dyslipidemia.

13-Oxo-9(Z),11(E),15(Z)-octadecatrienoic acid activates peroxisome proliferator-activated receptor γ in adipocytes.

Peroxisome proliferator-activated receptor (PPAR)γ is expressed in adipose tissue and plays a key role in the regulation of adipogenesis. PPARγ activators are known to have potent antihyperglycemic activity and are used to treat insulin resistance associated with diabetes. Therefore, many natural and synthetic agonists of PPARγ are used in the treatment of glucose disorders. In the present study, we found that 13-oxo-9(Z),11(E),15(Z)-octadecatrienoic acid (13-oxo-OTA), a linolenic acid derivative, is present in the extract of tomato (Solanum lycopersicum), Mandarin orange (Citrus reticulata), and bitter gourd (Momordica charantia). We also found that 13-oxo-OTA activated PPARγ and induced the mRNA expression of PPARγ target genes in adipocytes, thereby promoting differentiation. Furthermore, 13-oxo-OTA induced secretion of adiponectin and stimulated glucose uptake in adipocytes. To our knowledge, this is the first study to report that 13-oxo-OTA induces adipogenesis through PPARγ activation and to present 13-oxo-OTA as a valuable food-derived compound that may be applied in the management of glucose metabolism disorders.

Metabolomics reveal 1-palmitoyl lysophosphatidylcholine production by peroxisome proliferator-activated receptor α.

PPARα is well known as a master regulator of lipid metabolism. PPARα activation enhances fatty acid oxidation and decreases the levels of circulating and cellular lipids in obese diabetic patients. Although PPARα target genes are widely known, little is known about the alteration of plasma and liver metabolites during PPARα activation. Here, we report that metabolome analysis-implicated upregulation of many plasma lysoGP species during bezafibrate (PPARα agonist) treatment. In particular, 1-palmitoyl lysophosphatidylcholine [LPC(16:0)] is increased by bezafibrate treatment in both plasma and liver. In mouse primary hepatocytes, the secretion of LPC(16:0) increased on PPARα activation, and this effect was attenuated by PPARα antagonist treatment. We demonstrated that Pla2g7 gene expression levels in the murine hepatocytes were increased by PPARα activation, and the secretion of LPC(16:0) was suppressed by Pla2g7 siRNA treatment. Interestingly, LPC(16:0) activates PPARα and induces the expression of PPARα target genes in hepatocytes. Furthermore, we showed that LPC(16:0) has the ability to recover glucose uptake in adipocytes induced insulin resistance. These results reveal that LPC(16:0) is induced by PPARα activation in hepatocytes; LPC(16:0) contributes to the upregulation of PPARα target genes in hepatocytes and the recovery of glucose uptake in insulin-resistant adipocytes.

Localization of 9- and 13-oxo-octadecadienoic acids in tomato fruit.

We previously reported that the two peroxisome proliferator-activated receptor-α agonists, 9- and 13-oxo-octadecadienoic acids (oxo-ODAs), were found in the tomato fruit. However, their localization remains unknown. Herein, we showed that oxo-ODAs localize primarily in the fruit peel and their amount increases after the homogenization of the tomato fruit.