MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet
ABSTRACT Saturated fatty acids activate the cJun NH2-terminal kinase (JNK) pathway, resulting in chronic low-grade inflammation and the development of insulin resistance. Mixed-lineage kinase 3 (MLK3) is a mitogen activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in response to saturated fatty acids in vitro, however, the exact mechanism for diet-induced JNK activation in vivo is not known. Here we have used MLK3 deficient mice to examine the role of MLK3 in a saturated fat diet model of obesity. MLK3 KO mice fed a high fat diet enriched in medium chain saturated fatty acids for 16 weeks had decreased body fat compared to wild-type (WT) mice, due to increased energy expenditure, independently of food consumption and physical activity. Moreover, MLK3 deficiency attenuated palmitate-induced JNK activation and M1 polarization in bone marrow derived macrophages in vitro, and obesity-induced JNK activation, macrophage infiltration into adipose tissue and expression of pro-inflammatory cytokines in vivo. In addition, loss of MLK3 improved insulin resistance and decreased hepatic steatosis. Together, these data demonstrate that MLK3 promotes saturated fatty acid-induced JNK activation in vivo and diet-induced metabolic dysfunction.
SourceAvailable from: Amitabha Chaudhuri[Show abstract] [Hide abstract]
ABSTRACT: The M1 and M2 states of macrophage polarization are the two extremes of a physiologic/phenotypic continuum that is dynamically influenced by environmental signals. The M1/M2 paradigm is an excellent framework to understand and appreciate some of the diverse functions that macrophages perform. Molecular analysis of mouse and human macrophages indicated that they gain M1 and M2-related functions after encountering specific ligands in the tissue environment. In this perspective, I discuss the function of recepteur d'origine nantais (RON) receptor tyrosine kinase in regulating the M2-like state of macrophage activation Besides decreasing pro-inflammatory cytokine production in response to toll-like receptor-4 activation, macrophage-stimulating protein strongly suppresses nitric oxide synthase and at the same time upregulates arginase, which is the rate limiting enzyme in the ornithine biosynthesis pathway. Interestingly, RON signaling preserved some of the characteristics of the M1 state, while still promoting the hallmarks of M2 polarization. Therefore, therapeutic modulation of RON activity can shift the activation state of macrophages between acute and chronic inflammatory states.Frontiers in Immunology 10/2014; 5:546. DOI:10.3389/fimmu.2014.00546
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ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disorder in western countries and it is commonly associated with obesity and progression of the metabolic syndrome. Comprehending a wide spectrum of pathologic features, it is currently well recognized that a key point for the integrity of hepatocyte functionality in NAFLD is the progression from simple steatosis to non-alcoholic steatohepatitis (NASH). Indeed, activation of the innate immune system in response to hepatic metabolic stresses represents a central process that determines the evolution and the reversibility of liver damage. Despite of the burden of studies published in recent years, it is still intriguingly unclear how accumulation of lipids in hepatocytes triggers the activation of the inflammatory response leading to the recruitment of infiltrating cells of extra-hepatic origins. In this review we offer a general view on recent advances pointing out how different classes of lipids are able to specifically affect hepatocytes functionality and survival, thus differently influencing the organization of the hepatic immune response. On the other hand, we gathered recent studies intending to illustrate the basic mechanisms through which several non-parenchymal hepatic and extra-hepatic cell populations get activated in response to lipids. Finally, we indicate latter findings proposing how the immune system majorly contributes to the progression of NASH.
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ABSTRACT: Sustained JNK activation by saturated fatty acids plays a role in lipotoxicity and the pathogenesis of NASH. We have reported that the interaction of JNK with mitochondrial Sab leads to inhibition of respiration, increased ROS, cell death and hepatotoxicity. We tested whether this pathway underlies palmitic acid (PA)-induced lipotoxicity in hepatocytes. Primary mouse hepatocytes from adeno-shlacZ or adeno-shSab treated mice and Huh7 cells were used. In PMH, PA dose dependently up to 1mM stimulated oxygen consumption rate (OCR) due to mitochondrial β-oxidation. At ⩾1.5mM, PA gradually reduced OCR, followed by cell death. Inhibition of JNK, caspases or treatment with antioxidant butylated hydroxyanisole (BHA) protected PMH against cell death. Sab knockdown or a membrane permeable Sab blocking peptide prevented PA-induced mitochondrial impairment, but inhibited only the late phase of both JNK activation (beyond 4 hours) and cell death. PA increased P-PERK and downstream target CHOP in PMH but failed to activate the IRE-1α arm of the UPR. However, Sab silencing did not affect PA- induced PERK activation. Conversely, specific inhibition of PERK prevented JNK activation and cell death, indicating a major role upstream of JNK activation. The effect of P-JNK on mitochondria plays a key role in PA-mediated lipotoxicity. The interplay of P-JNK with mitochondrial Sab leads to impaired respiration, ROS production, sustained JNK activation, and apoptosis. Copyright © 2015. Published by Elsevier B.V.Journal of Hepatology 02/2015; DOI:10.1016/j.jhep.2015.01.032 · 10.40 Impact Factor