L-carnitine ameliorates the liver inflammatory response by regulating carnitine palmitoyltransferase I-dependent PPARγ signaling.

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The liver is crucial for systemic inflammation in cancer cachexia. Previous studies have shown that L-carnitine, as the key regulator of lipid metabolism, exerts an anti-inflammatory effect in several diseases, and ameliorates the symptoms of cachexia by regulating the expression and activity of carnitine palmitoyltransferase (CPT) in the liver. However, the effect of L-carnitine on the liver inflammatory response in cancer cachexia remains to be elucidated. The aim of the present study was to examine the role of the CPT I-dependent peroxisome proliferator-activated receptor (PPAR)γ signaling pathway in the ameliorative effect of L-carnitine on the liver inflammatory response. This was investigated in a colon-26 tumor-bearing mouse model with cancer cachexia. Liver sections were immunohistochemically analyzed, and mRNA and protein levels of representative molecules of the CPT-associated PPARγ signaling pathway were assessed using PCR and western blot analysis, respectively. The results showed that oral administration of L-carnitine in these mice improved hepatocyte necrosis, liver cell cord derangement and hydropic or fatty degeneration of the liver cells in the liver tissues, decreased serum levels of malondialdehyde, increased serum levels of superoxide dismutase and glutathione peroxidase, and elevated the expression levels of PPARα and PPARγ at the mRNA and protein levels. These changes induced by L-carnitine were reversed by treatment with etomoxir, an inhibitor of CPT I. The inhibitory effect of L-carnitine on the increased expression level of nuclear factor (NF)-κB p65 in the peripheral blood mononuclear cells was markedly weakened by GW9662, a selective inhibitor of PPAR-γ. GW9662 also eliminated the inhibitory effect of L-carnitine on the expression of cyclooxygenase-2 (Cox-2) in the liver, and on the serum expression levels of pro-inflammatory prostaglandin E2, C-reactive protein, tumor necrosis factor-α and interleukin-6 in the cancer cachexia model mice. This reversing effect of GW9662 on L-carnitine was restored by pyrrolidine dithiocarbamate, a specific inhibitor of NF-κB signaling. Taken together, these results demonstrated that L-carnitine ameliorated liver inflammation and serum pro-inflammatory markers in cancer cachexia through regulating CPT I-dependent PPARγ signaling, including the downstream molecules of NF-κB p65 and Cox-2.