Low expression of IL-18 and IL-18 receptor in human skeletal muscle is associated with systemic and intramuscular lipid metabolism-Role of HIV lipodystrophy

PLoS One. 2018 Jan 17;13(1):e0186755. doi: 10.1371/journal.pone.0186755. eCollection 2018.

Abstract

Introduction: Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL-18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18 receptor (R) expression would be altered in patients with HIV-lipodystrophy.

Design and methods: Twenty-three HIV-infected patients with LD and 15 age-matched healthy controls were included in a cross-sectional study. Biopsies from the vastus lateralis muscle were obtained and IL-18 and IL-18R mRNA expression were measured by real-time PCR and sphingolipids (ceramides, sphingosine, sphingosine-1-Phosphate, sphinganine) were measured by HPLC. Insulin resistance was assessed by HOMA and the insulin response during an OGTT.

Results: Patients with HIV-LD had a 60% and 54% lower level of muscular IL-18 and IL-18R mRNA expression, respectively, compared to age-matched healthy controls. Patients with HIV-LD had a trend towards increased levels of ceramide (18.3±4.7 versus 14.8±3.0,p = 0.06) and sphingosine (0.41±0.13 versus 0.32±0.07, and lower level of sphinganine (p = 0.06). Low levels of muscle IL-18 mRNA correlated to high levels of ceramides (r = -0.31, p = 0.038) and sphingosine-1P (r = -0.29, p = 0.046) in skeletal muscle, whereas such a correlation was not found in healthy controls. Low expression of IL-18 mRNA in skeletal muscle correlated to elevated concentration of circulating triglycerides (Rp = -0.73, p<0.0001). Neither muscle expression of IL-18 mRNA or ceramide correlated to parameters of insulin resistance.

Conclusion: IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • HIV Infections / complications
  • HIV Infections / metabolism*
  • Humans
  • Interleukin-18 / metabolism*
  • Lipid Metabolism*
  • Lipodystrophy / complications
  • Lipodystrophy / metabolism*
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism*
  • Receptors, Interleukin-18 / metabolism*

Substances

  • Interleukin-18
  • Receptors, Interleukin-18

Grants and funding

This work was supported by the Danish National Research Foundation (DNRF55). The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. This study was further supported by grants from the Lundbeck foundation, the Danish AIDS Foundation, the Novo Nordisk Foundation, Direktør Emil Hertz og Hustru Inger Hertz´ Fond, Direktør Jacob Madsen og Hustru Olga Madsens Fond, Fonden for Lægevidenskabens Fremme. CIM/CFAS is a member of DD2 - the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724). The funders had a no role in study design, data collection adn analysis, decision to publish, or prepation of the manuscript.