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.