Liver macrophages regulate systemic metabolism through non-inflammatory factors

Morgantini, Cecilia; Jager, Jennifer; Li, Xidan; Levi, Laura; Azzimato, Valerio; Sulen, André; Barreby, Emelie; Xu, Connie; Tencerová, Michaela; Näslund, Erik; Kumar, Chanchal; Verdeguer, Francisco; Straniero, Sara; Hultenby, Kjell; Björkström, Niklas K.; Ellis, Ewa; Rydén, Mikael; Kutter, Claudia; Hurrell, Tracey; Lauschke, Volker M.; Boucher, Jérémie; Tomčala, Aleš; Krejčová, Gabriela; Bajgar, Adam; Aouadi, Myriam

doi:10.1038/s42255-019-0044-9

Cited by 82 publications

(75 citation statements)

References 72 publications

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“…Surprisingly, unbiased transcriptomic analysis revealed no differences in terms of expression of genes associated with a pro-inflammatory signature, between liver macrophages from lean and obese patients (similar data were obtained from mice fed an HFD for 9 weeks). Metabolic impairments are not associated with a pro-inflammatory activation of liver macrophages (78). However, the transcriptomic inflammatory signature is indeed variant between the stages of benign steatosis and NASH.…”

Section: Liver Macrophages In Metabolic Inflammationmentioning

confidence: 91%

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

et al. 2020

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Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.

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Section: Liver Macrophages In Metabolic Inflammationmentioning

confidence: 91%

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

et al. 2020

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“…PHH spheroids were also recently used to interrogate the protective role of nitrite in reducing chemically and metabolically induced steatosis . Moreover, spheroid cultures were used to reveal the critical role of insulin‐like growth factor binding protein 7, a factor secreted by liver macrophages that binds to the hepatocyte insulin receptor and induces lipogenesis and gluconeogenesis, thus revealing how macrophages contribute to insulin resistance independent of inflammation …”

Section: Applications Of Advanced Primary Human Hepatocyte Culture Momentioning

confidence: 99%

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Lauschke

Shafagh

Hendriks

et al. 2019

Biotechnology Journal

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109

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Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which the cells exhibit an in vivo‐like phenotype, often achieved by reconstitution of appropriate cellular interactions. Multiple different models have been presented that differ in the cells utilized, media, and culture conditions. Furthermore, several technologically different approaches have been presented including bioreactors, chips, and plate‐based systems in fluidic or static media constituting of chemically diverse materials. Using such models, the ability to predict drug metabolism, drug toxicity, and liver functionality have increased tremendously as compared to conventional in vitro models in which cells are cultured as 2D monolayers. Here, the authors highlight important considerations for microphysiological systems for primary hepatocyte culture, review current culture paradigms, and discuss their opportunities for studies of drug metabolism, hepatotoxicity, liver biology, and disease.

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“…We have also demonstrated that, during obesity, LMs produce non-inflammatory factors able to regulate insulin sensitivity but nonetheless display signs of oxidative stress. Indeed, transcriptomic profiling showed that several metabolic pathways involved in ROS/RNS production such as the tricarboxylic acid cycle (TCA) cycle and oxidative phosphorylation (OXPHOS) were dysregulated in the LMs of obese compared to control mice (10). We therefore hypothesized that LMs may regulate oxidative stress independently of their inflammatory status in obesity-induced insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance

et al. 2020

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Obesity and insulin resistance are risk factors for nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. Because no approved medication nor an accurate and noninvasive diagnosis is currently available for NAFLD, there is a clear need to better understand the link between obesity and NAFLD. Lipid accumulation during obesity is known to be associated with oxidative stress and inflammatory activation of liver macrophages (LMs). However, we show that although LMs do not become proinflammatory during obesity, they display signs of oxidative stress. In livers of both humans and mice, antioxidant nuclear factor erythroid 2–related factor 2 (NRF2) was down-regulated with obesity and insulin resistance, yielding an impaired response to lipid accumulation. At the molecular level, a microRNA-targeting NRF2 protein, miR-144, was elevated in the livers of obese insulin-resistant humans and mice, and specific silencing of miR-144 in murine and human LMs was sufficient to restore NRF2 protein expression and the antioxidant response. These results highlight the pathological role of LMs and their therapeutic potential to restore the impaired endogenous antioxidant response in obesity-associated NAFLD.

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Liver macrophages regulate systemic metabolism through non-inflammatory factors

Cited by 82 publications

References 72 publications

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Liver macrophages inhibit the endogenous antioxidant response in obesity-associated insulin resistance

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