TY - JOUR
T1 - P38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration
AU - González-Terán, Bárbara
AU - Matesanz, Nuria
AU - Nikolic, Ivana
AU - Verdugo, María Angeles
AU - Sreeramkumar, Vinatha
AU - Hernández-Cosido, Lourdes
AU - Mora, Alfonso
AU - Crainiciuc, Georgiana
AU - Sáiz, María Laura
AU - Bernardo, Edgar
AU - Leiva-Vega, Luis
AU - Rodríguez, Elena
AU - Bondía, Victor
AU - Torres, Jorge L.
AU - Perez-Sieira, Sonia
AU - Ortega, Luis
AU - Cuenda, Ana
AU - Sanchez-Madrid, Francisco
AU - Nogueiras, Rubén
AU - Hidalgo, Andrés
AU - Marcos, Miguel
AU - Sabio, Guadalupe
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - 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 (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ 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 p38γ/δ-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, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy. Synopsis Mice lacking p38γ/δ in myeloid cells are protected against diet-induced fatty liver. This effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes. Expression of p38δ and p38γ is elevated in the liver from patients with non-alcoholic fatty liver disease (NAFLD). p38γ/δ KO and myeloid-specific p38γ/δ cKO mice are resistant to hepatic steatosis induced by high-fat diet or methionine-choline-deficient diet. p38γ/δ control neutrophil migration to the damaged liver. Migration of neutrophils to the liver is necessary for the development of steatosis. Mice lacking p38γ/δ in myeloid cells are protected against diet-induced fatty liver. This effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.
AB - 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 (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ 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 p38γ/δ-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, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy. Synopsis Mice lacking p38γ/δ in myeloid cells are protected against diet-induced fatty liver. This effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes. Expression of p38δ and p38γ is elevated in the liver from patients with non-alcoholic fatty liver disease (NAFLD). p38γ/δ KO and myeloid-specific p38γ/δ cKO mice are resistant to hepatic steatosis induced by high-fat diet or methionine-choline-deficient diet. p38γ/δ control neutrophil migration to the damaged liver. Migration of neutrophils to the liver is necessary for the development of steatosis. Mice lacking p38γ/δ in myeloid cells are protected against diet-induced fatty liver. This effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.
KW - diabetes
KW - inflammation
KW - obesity
KW - steatosis
KW - stress kinases
UR - https://www.scopus.com/pages/publications/84959320195
U2 - 10.15252/embj.201591857
DO - 10.15252/embj.201591857
M3 - Article
C2 - 26843485
AN - SCOPUS:84959320195
SN - 0261-4189
VL - 35
SP - 536
EP - 552
JO - EMBO Journal
JF - EMBO Journal
IS - 5
ER -