p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration

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 p38 mitogen-activated kinases (p38 gamma and p38 delta) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38 delta is elevated in livers of obese patients with NAFLD and that mice lacking p38 gamma/delta 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 p38 gamma/delta-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, p38 gamma and p38 delta in myeloid cells provide a potential target for NAFLD therapy.