SUMMARY Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4 pos Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4 neg macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9 , and Gpmnb ; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2 -expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 ( Ccr2 )-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.

ObjectiveIntramyocellular lipid (IMCL) storage negatively associates with insulin resistance, albeit not in endurance-trained athletes. We investigated the putative contribution of lipid droplet (LD) morphology and subcellular localization to the so-called athlete's paradox.MethodsWe performed quantitative immunofluorescent confocal imaging of muscle biopsy sections from endurance Trained, Lean sedentary, Obese, and Type 2 diabetes (T2DM) participants (n = 8/group). T2DM patients and Trained individuals were matched for IMCL content. Furthermore we performed this analysis in biopsies of T2DM patients before and after a 12-week exercise program (n = 8).ResultsWe found marked differences in lipid storage morphology between trained subjects and T2DM: the latter group mainly store lipid in larger LDs in the subsarcolemmal (SS) region of type II fibers, whereas Trained store lipid in a higher number of LDs in the intramyofibrillar (IMF) region of type I fibers. In addition, a twelve-week combined endurance and strength exercise program resulted in a LD phenotype shift in T2DM patients partly towards an ‘athlete-like’ phenotype, accompanied by improved insulin sensitivity. Proteins involved in LD turnover were also more abundant in Trained than in T2DM and partly changed in an ‘athlete-like’ fashion in T2DM patients upon exercise training.ConclusionsOur findings provide a physiological explanation for the athlete's paradox and reveal LD morphology and distribution as a major determinant of skeletal muscle insulin sensitivity.

BackgroundExcess storage of lipids in ectopic tissues, such as skeletal muscle, liver, and heart, seems to associate closely with metabolic abnormalities and cardiac disease. Intracellular lipid storage occurs in lipid droplets, which have gained attention as active organelles in cellular metabolism. Recent developments in high-resolution microscopy and microscopic spectroscopy have opened up new avenues to examine the physiology and biochemistry of intracellular lipids.Scope of reviewThe aim of this review is to give an overview of recent technical advances in microscopy, and its application for the visualization, identification, and quantification of intracellular lipids, with special focus to lipid droplets. In addition, we attempt to summarize the probes currently available for the visualization of lipids.Major conclusionsThe continuous development of lipid probes in combination with the rapid development of microscopic techniques can provide new insights in the role and dynamics of intracellular lipids. Moreover, in situ identification of intracellular lipids is now possible and promises to add a new dimensionality to analysis of lipid biochemistry, and its relation to (patho)physiology.

No abstract

The essential function of sterol regulatory element-binding proteins (SREBPs) in cellular lipid metabolism and homeostasis has been recognized for a long time, and the basic biological pathway involving SREBPs has been well described; however, a rapidly growing number of studies reveal the complex regulation of these SREBP transcription factors at multiple levels. This regulation allows the integration of signals of diverse pathways involving nutrients, contributing to cellular lipid and energy homeostasis. This review attempts to integrate this knowledge. The description of the SREBP pathway is Web-linked as it refers to the online version of the pathway on wikipathways.org, which is interactively linked to genomics databases and literature. This allows a more extensive study of the pathway through reviewing these links.