p38c and p38d reprogram liver metabolism by modulating neutrophil infiltration
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چکیده
Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38mitogen-activated kinases (p38c and p38d) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38d is elevated in livers of obese patients with NAFLD and that mice lacking p38c/d in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38c/d-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38c and p38d in myeloid cells provide a potential target for NAFLD therapy.
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تاریخ انتشار 2016