High-Mobility Group Box 1 Disrupts Metabolic Function with Cigarette Smoke Exposure in a Ceramide-Dependent Manner

Abstract

We have previously found that cigarette smoke disrupts metabolic function, in part, by increasing muscle ceramide accrual. To further our understanding of this, we sought to determine the role of the cytokine high-mobility group box 1 (HMGB1), which is increased with smoke exposure, in smoke-induced muscle metabolic perturbations. To test this theory, we determined HMGB1 from lungs of human smokers, as well as from lung cells from mice exposed to cigarette smoke. We also treated cells and mice directly with HMGB1, in the presence or absence of myriocin, an inhibitor of serine palmitoyltransferase, the rate-limiting enzyme in ceramide biosynthesis. Outcomes included assessments of insulin resistance and muscle mitochondrial function. HMGB1 was significantly increased in both human lungs and rodent alveolar macrophages. Further testing revealed that HMGB1 treatment elicited a widespread increase in ceramide species and reduction in myotube mitochondrial respiration, an increase in reactive oxygen species, and reduced insulin-stimulated Akt phosphorylation. Inhibition of ceramide biosynthesis with myriocin was protective. In mice, by comparing treatments of HMGB1 injections with or without myriocin, we found that HMGB1 injections resulted in increased muscle ceramides, especially C16 and C24, which were necessary for reduced muscle mitochondrial respiration and compromised insulin and glucose tolerance. In conclusion, HMGB1 may be a necessary intermediate in the ceramide-dependent metabolic consequences of cigarette smoke exposure.

Downregulation of Lysosomal Acid Ceramidase Mediates HMGB1-Induced Migration and Proliferation of Mouse Coronary Arterial Myocytes

“…et al, 2017;Anroedh et al, 2018;Meeusen et al, 2018). In mice, HMGB1 injections were noted to increase ceramides in muscle cells, especially C16 and C24 ceramides, enhance reactive oxygen species (ROS) production, and disrupt mitochondrial and insulin function, effects were alleviated with ceramide inhibition (Taylor et al, 2017). The present study also demonstrated that HMGB1 and NOE similarly increased long-chain ceramides including C14, C16, C18, C20, C22, and C24 ceramides.…”

Ceramide: a novel inducer for neural tube defects

“…Two potential hypotheses for this reduced proliferation are (a) an overall reduction in cellular metabolism due to C2 treatment impacting mitochondrial function, and (b) ciliary disruption due to C2 treatment disrupts cellular functionality and division. Ceramides are implicated in reducing the mitochondrial respiration of skeletal muscle cells, 71,72 and several lines of study have indicated a potential role of primary cilium in the development of NTDs. [73][74][75][76] Ceramides are reported to regulate the generation and elongation of primary cilium.…”

Diesel Exhaust Particle Exposure Compromises Alveolar Macrophage Mitochondrial Bioenergetics

“…One of the earliest observations of this interaction was the production of inflammatory cytokines from adipose, a prototypical metabolic tissue, which resulted in defects in systemic sensitivity to insulin, a prototypical metabolic hormone [1]. Macrophages, whether adipose or otherwise, are highly relevant to this process, with a prominent line of evidence suggesting that macrophage activation provides an inflammatory “spark” that ignites systemic downstream cardiometabolic complications [2,3,4]. Insofar as the lung, being one of two sites of direct environment–host interaction, is enriched with macrophages, evidence implicating the macrophage and its inflammatory actions in metabolic disruption in response to inhaled noxious stimuli is strong [5].…”

“…Unsurprisingly, consistent DEP inhalation is implicated with several cardiorespiratory disorders and mortality [7], with both epidemiological [8] and molecular [7] evidence indicating a primary role of the lung macrophage. At least some of the pathology associated with noxious stimuli exposure is a result of macrophage-induced cytokine release, which has been a focus of earlier work from our lab [4,9,10].…”

“…Interestingly, while mitochondria are an understandably prominent focus in the context of exploring metabolic health, its influence in mediating macrophage-induced metabolic disruption is lacking and the limited evidence overwhelmingly exists in non-lung tissues. We have previously found that cigarette smoke exposure alters whole body metabolic function [4,9,11], including mitochondria-specific consequences [3]. However, while cigarette smoke exposure is declining in many parts of the world, the increasing industrialization is leading to evermore exposure to diesel exhaust combustion [12].…”