p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration

Abstract

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 (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.

ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model

“…Both p38 and JNK can promote fibrogenic gene expression through phosphorylating nuclear transcription factors ATF2 and c-Jun (31-35), respectively. In mouse models of NAFLD and liver fibrosis, JNK promotes production of proinflammatory cytokines such as TNF-α; IL-1β; IL-6; chemokines such as CCL2, CCL3, and CCL4; and profibrotic mediators such as TGF-β (36,37). In hepatic stellate cells, JNK signaling has been shown to be required for differentiation into myofibroblasts (38).…”

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology

“…Indeed, a phase I trial of the p38 alpha inhibitor LY3007113 failed because of unacceptable toxicity (52). In contrast, p38 gamma and delta double-knockouts are viable, and these mice have been used to demonstrate specific inflammatory roles for these kinases within macrophages, T cells, and myeloid cells (53,54). These studies point to biomarkers and cell types for further analysis with p38 gamma-and delta-biased inhibitors such as AD80.…”

Foundations of Immunometabolism and Implications for Metabolic Health and Disease

“…Beyond JNK and IKK, multiple other intermediate signaling kinases are also involved in linking inflammatory pathways to insulin action, including PKC, PKR, CAMK, AMPK, mTOR, JAK, PKA, ERK, p38 and other MAP kinases (Copps and White, 2012; Fullerton et al, 2013; Gonzalez-Teran et al, 2016; Hotamisligil, 2006). These kinases can be activated by insulin, in response to lipid mediators, cytokines, or by sympathetic stimulation, and the resultant phosphorylation of the insulin signaling pathway components can be either activating or inhibitory.…”