Abstract
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.
Highlights
PPAR␣ is well known as a master regulator of lipid metabolism
We confirmed that plasma TG was decreased, and the expression of PPAR␣ target genes in the liver was increased by bezafibrate treatment for 4 weeks (Table 1)
To identify the metabolites that were influenced by PPAR␣ activation, we investigated the plasma metabolites profile in mice treated with bezafibrate for 4 weeks by metabolome analysis based on LC/MS and by using metabolite databases, including the Kyoto Encyclopedia of Genes and Genomes and Lipid Maps
Summary
PPAR␣ activation enhances fatty acid oxidation and decreases the levels of circulating and cellular lipids in obese diabetic patients. We demonstrated that Pla2g7 gene expression levels in the murine hepatocytes were increased by PPAR␣ activation, and the secretion of LPC(16:0) was suppressed by Pla2g7 siRNA treatment. During PPAR␣ activation, transcription of PPAR␣regulated genes [e.g., carnitine-O-palmitoyltransferase 1 (CPT1) and acyl-CoA oxidase (ACO)] is stimulated and -oxidation is activated [12,13,14] This activation and increased PPAR␣ sensing in the liver result in increased energy burning and reduced fat storage [15]. It has been reported that PPAR␣ activation enhances fatty acid oxidation and decreases the levels of circulating and cellular lipids in obese diabetic patients [9, 16]. PPAR␣ target genes are widely known, little is known about the variation of metabolites in plasma and liver during the activation of these genes
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