Correction: 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.

[This corrects the article DOI: 10.1371/journal.pone.0186755.].

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.

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.

Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-ß-hydroxybutyratemia in post-absorptive healthy males.

CONTEXT: Ketone bodies are substrates during fasting and when on a ketogenic diet not the least for the brain and implicated in the management of epileptic seizures and dementia. Moreover, D-ß-hydroxybutyrate (HOB) is suggested to reduce blood glucose and fatty acid levels. OBJECTIVES: The objectives of this study were to quantitate systemic, cerebral, and skeletal muscle HOB utilization and its effect on energy metabolism. DESIGN: Single trial. SETTING: Hospital. PARTICIPANT: Healthy post-absorptive males (n = 6). INTERVENTIONS: Subjects were studied under basal condition and three consecutive 1-hour periods with a 3-, 6-, and 12-fold increased HOB concentration via HOB infusion. MAIN OUTCOME MEASURES: Systemic, cerebral, and skeletal muscle HOB kinetics, oxidation, glucose turnover, and lipolysis via arterial, jugular, and femoral venous differences in combination with stable isotopically labeled HOB, glucose, and glycerol, infusion. RESULTS: An increase in HOB from the basal 160-450 µmol/L elicited 14 ± 2% reduction (P = .03) in glucose appearance and 37 ± 4% decrease (P = .03) in lipolytic rate while insulin and glucagon were unchanged. Endogenous HOB appearance was reduced in a dose-dependent manner with complete inhibition at the highest HOB concentration (1.7 mmol/L). Cerebral HOB uptake and subsequent oxidation was linearly related to the arterial HOB concentration. Resting skeletal muscle HOB uptake showed saturation kinetics. CONCLUSION: A small increase in the HOB concentration decreases glucose production and lipolysis in post-absorptive healthy males. Moreover, cerebral HOB uptake and oxidation rates are linearly related to the arterial HOB concentration of importance for modifying brain energy utilization, potentially of relevance for patients with epileptic seizures and dementia.