We read with great interest the article by Orellana-Gavalda etal. about the ameliorating effects of long-term hepatic gene transfer of carnitine palmitoyltransferase 1A (CPT1A) on obesity-induced hepatic steatosis, diabetes, and insulin resistance.1 The authors observed increased lipid oxidation mediated by a significant up-regulation of liver CPT1A messenger RNA (mRNA). This effect not only improved lipid and glucose metabolism, but also had direct impact on liver inflammatory stress triggered by high-fat diet (HFD) feeding.
Orellana-Gavalda etal. suggest that increasing hepatic CPT1A expression is a valid in vivo strategy to reduce obesity-related complications. In a rat model of nonalcoholic fatty liver disease (NAFLD), we observed fairly similar results with indomethacin, a dual pharmacological inhibitor of cyclooxygenase 1 (COX1) (prostaglandin H synthase 1 [PTGS1]) and COX2 (PTGS2). We evaluated the effect of the drug on reversing fatty liver, and we also explored the impact on liver mRNA expression of several lipogenic and glucogenic genes, and nuclear receptors. Rats were given a HFD2 for 8 weeks, and after this period, animals were randomly divided into two groups. For 4 weeks, along with access to HFD, one group received indomethacin (n = 5 rats, 1 mg/day) every 24hours, and the second group (n = 5 rats) was fed with HFD; a control group (6 rats) was fed with standard chow diet (SCD) for 12 weeks. We observed that indomethacin significantly revert fatty liver disease (Fig. 1). The most remarkable effects of COX inhibition by indomethacin in the HFD group in comparison with the SCD group were: a 230% increase of liver expression of CPTA1 mRNA, a 100% increase of liver abundance of PCK1 mRNA (phosphoenolpyruvate carboxykinase, the main control point for the regulation of gluconeogenesis), and an increase of 84% ofPPARα mRNA (peroxisome proliferator-activated receptor alpha,a transcription factor that controls the expression of genes encodingfatty acid oxidation enzymes and mitochondrial fatty acid oxidation) (Fig. 1).
As far as we know, we show for the first time that indomethacin is able to increase liver CPT1A mRNA. We can not explain the exact mechanism by which the drug influences liver CPT1A expression, although an inhibitory effect of a COX product on the gene expression is an obvious option, but we agree with Orellana-Gavalda etal. that liver CPT1A is a prime target to increase beta-oxidation of hepatic long-chain fatty acids. Other explanations are probable. Indomethacin was regarded as a dual PPARγ/PPARα ligand.3 In addition, the 5′-flanking region of COX2 has several potential transcription regulatory sequences, including CCAAT/enhancer binding protein motif (a gene that specifically regulates hepatic gluconeogenesis and lipogenesis4) and two nuclear factor-κB sites (a key modulator of liver injury in NAFLD). Hence, these observations may explain the beneficial effects of indomethacin on NAFLD. In summary, our results represent proof of principle that pharmacological COX inhibition may provide a novel approach for reversing fatty liver by modulating the liver CPT1A mRNA expression. These results also add some clues about the potential role of the inducible COX2 and its proinflammatory prostaglandin products in metabolic disorders, including NAFLD.