Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism

Figures

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  Fig. 1. Macrophages in obese adipose tissue. In obesity, chemokines stimulate the infiltration of macrophages into the AT. Various danger molecules and fatty acids promote a pro-inflammatory phenotype in ATMs, which contributes to the development of a persistent, low-grade inflammation. Pro-inflammatory mediators secreted by ATMs induce insulin resistance by signalling through the JNK and IKK-β pathways. Inhibition of lipid droplet-associated peptides, such as fsp27, enhance lipolysis. Downstream, insulin resistance and lipolysis lead to ectopic lipid accumulation in various organs, including the liver. AT, adipose tissue; ATMs, adipose tissue macrophages; IRS, insulin receptor substrates; TLRs, Toll-like receptors.

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  Fig. 2. Metabolic coordination of macrophage activation. (A) Inflammatory (M1) activation. LPS and/or IFNγ stimulation increases glucose consumption, which is converted to lactate instead of entering the Krebs cycle as pyruvate. The pentose phosphate pathway and fatty acid synthesis are activated to generate biomolecules. These metabolic alterations depend in part on HIF-1α, which stimulates glucose entry and conversion to lactate and directly promotes M1 gene expression. (B) M2 polarization depends on increased β-oxidation and oxidative phosphorylation of fatty acids. This is fuelled by the uptake and lysosomal breakdown of TAGs and the de novo synthesis from glucose. PPARγ and PPARδ bind these intracellular lipids and are key effectors of the metabolic and phenotype switch upon IL-4 stimulation. (C) Macrophages display a metabolically activated phenotype upon stimulation with SFAs. In the adipose tissue, one mechanism of SFA uptake is through the digestion of dead adipocytes at crown-like structures. Binding of LPS primes macrophages towards the pro-inflammatory effects of SFAs, leading to a distinct macrophage phenotype that secretes inflammatory mediators such as IL-1β. PPARγ has a…

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  Fig. 3. Macrophage-mediated inflammation as a therapeutic target in NASH progression. In NASH, KCs are activated by bacterial LPS and by danger signals from fat-laden hepatocytes, leading to the production of pro-inflammatory mediators that promote disease progression. Chemokines induce the infiltration of monocytes, which differentiate into monocyte-derived macrophages. These cells contribute to the progression of NASH by aggravating hepatic steatosis, activating stellate cells and promoting fibrosis. Ly6Chigh macrophages can mature into Ly6Clow restorative macrophages that endorse disease resolution through secretion of anti-inflammatory cytokines and collagen degrading factors. Monocyte-derived macrophages can differentiate into KCs (monocyte-derived KCs, MoKC), although it is unclear at this point if this population is capable of long-term self-renewal or if they are short-lived. Selected drugs that target inflammatory pathways and which are currently under investigation are indicated. HRG, histidine-rich glycoprotein; KC, Kupffer cell; LPS, lipopolysaccharide; MDA, malonyldialdehyde; MMPs, matrix metalloproteinases; MoKC, monocyte-derived Kupffer cell; NASH, non-alcoholic…