Background:
Toll-like receptor 4 (TLR4) is an innate proinflammatory mediator found in a wide variety of cell types including cardiomyocytes. The autophagy-lysosome pathway, a major pathway governing protein and organelle degradation and recycling, plays a pivotal role in maintaining cardiac homeostasis under physiological and pathological conditions. The aim of this study was to evaluate the impact of TLR4 knockout (TLR4
-/-
) on high fat diet (HFD)-induced cardiomyopathy and the underlying mechanisms involved, with a focus on inflammation and autophagy pathways.
Methods:
Wild type (WT) and TLR4
-/-
mice were fed on low fat diet (LFD) or HFD for 12 weeks. Metabolic rate and glucose tolerance were measured in WT and TLR4
-/-
mice at the end of fat diet intake. Echocardiographic, cardiomyocyte mechanical function, morphological feature, aconitase activity, ROS generation and immunoblotting were assessed.
Results:
TLR4
-/-
did not prevent HFD-induced obesity and insulin resistance, as evidenced by body weight gain and glucose intolerance. In addition, there was little difference in metabolic parameters (V
O2
, V
CO2
, RER, energy expenditure and physical activity) between WT and TLR4
-/-
mice fed with HFD. However, TLR4
-/-
alleviated HFD-elicited cardiac hypertrophy and contractile dysfunction. HFD-feeding caused extensive mitochondrial injury and ROS generation, which were alleviated by TLR4
-/-
. TLR4
-/-
dramatically attenuated inflammation signaling (up-regulated p-IKβ, NF-κB and p-JNK) in the face of HFD intake. Cardiac autophagy was significantly suppressed by HFD, as evidenced by up-regulated p-mTOR, down-regulated p-AMPK, Atg5, Atg12, LC3BII, and up-regulated P62 in HFD-induced cardiomyopathy. Furthermore, in vitro study revealed that the TLR4 inhibitor-TAK-242 reconciled palmitic acid-induced cardiomyocyte autophagy and contractile anomalies.
Conclusions:
Our results suggested that TLR4
-/-
does not prevent HFD-induced obesity and insulin resistance. However, TLR4 is a culprit factor for cardiac dysfunction following HFD intake. The cardioprotective effect of TLR4
-/-
against HFD-induced cardiomyopathy is associated with attenuation of myocardial inflammation and recovery of cardiac autophagy activity.