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

International Journal of Molecular Sciences
Oliver J TaylorBenjamin T Bikman

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 ...Continue Reading

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Citations

Nov 25, 2017·The Biochemical Journal·Blake W DallonBenjamin T Bikman
Aug 8, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Micah M RossMichael R Stark
Sep 14, 2018·Current Vascular Pharmacology·Saeid GolbidiIsmail Laher
Aug 4, 2018·International Journal of Molecular Sciences·Brian A ParkerBenjamin T Bikman
Nov 14, 2019·International Journal of Molecular Sciences·Jonathan L GibbsBenjamin T Bikman
Jul 23, 2020·Medicine and Science in Sports and Exercise·Rongsong LiHarry B Rossiter

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Methods Mentioned

BETA
protein assay
ELISA
PCR

Software Mentioned

PeakView
Lipid Explorer
Graphpad Prism
Analyst

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