Spaceflight Activates Lipotoxic Pathways in Mouse Liver

Spaceflight affects numerous organ systems in the body, leading to metabolic dysfunction that may have long-term consequences. Microgravity-induced alterations in liver metabolism, particularly with respect to lipids, remain largely unexplored. Here we utilize a novel systems biology approach, combining metabolomics and transcriptomics with advanced Raman microscopy, to investigate altered hepatic lipid metabolism in mice following short duration spaceflight. Mice flown aboard Space Transportation System -135, the last Shuttle mission, lose weight but redistribute lipids, particularly to the liver. Intriguingly, spaceflight mice lose retinol from lipid droplets. Both mRNA and metabolite changes suggest the retinol loss is linked to activation of PPARα-mediated pathways and potentially to hepatic stellate cell activation, both of which may be coincident with increased bile acids and early signs of liver injury. Although the 13-day flight duration is too short for frank fibrosis to develop, the retinol loss plus changes in markers of extracellular matrix remodeling raise the concern that longer duration exposure to the space environment may result in progressive liver damage, increasing the risk for nonalcoholic fatty liver disease

Characterization of expressed human meibum using hyperspectral stimulated Raman scattering microscopy.

PurposeThis study examined whether hyperspectral stimulated Raman scattering (hsSRS) microscopy can detect differences in meibum lipid to protein composition of normal and evaporative dry eye subjects with meibomian gland dysfunction.MethodsSubjects were evaluated for tear breakup time (TBUT), staining, meibum expression and gland dropout. Expressed meibum was analyzed using SRS vibrational signatures in the CH stretching region (2800-3050 cm-1). Vertex component analysis and K-means clustering were used to group the spectral signatures into four fractions containing high lipid (G1) to high protein (G4).ResultsThirty-three subjects could be statistically analyzed using pooled meibum (13 with stable tear films (TBUTs > 10 s) and 20 with unstable tear films (TBUTs ≤ 10 s). Significant differences in meibum from subjects with unstable vs. stable TBUTs were found for the G1 fraction (medians 0.164 and 0.020, respectively; p = 0.012) and the G2 fraction (medians 0.244 and 0.272, respectively; p = 0.045). No differences were observed for the G3 and G4 fractions. Single orifice samples were not significantly different vs. pooled samples from the fellow eye, and eyelid sector samples (nasal, central and temporal) G2:G3 fractional components were not significantly different (p = 0.449). Spearman analysis suggested a significant inverse correlation between G1 fraction and TBUT (R = -0.351; p = 0.045).ConclusionshsSRS microscopy allows compositional analysis of expressed meibum from humans which correlated to changes in TBUT. These findings support the hypothesis that hsSRS may be useful in classifying meibum quality and evaluating the effects of therapy

Correction: Spaceflight Activates Lipotoxic Pathways in Mouse Liver.

[This corrects the article DOI: 10.1371/journal.pone.0152877.]

Correction: Spaceflight Activates Lipotoxic Pathways in Mouse Liver.

[This corrects the article DOI: 10.1371/journal.pone.0152877.]

Correction: Spaceflight Activates Lipotoxic Pathways in Mouse Liver.

[This corrects the article DOI: 10.1371/journal.pone.0152877.]

Food intake and body composition measurements for AEM controls and FLT mice.

<p>Food intake and body composition measurements for AEM controls and FLT mice.</p

Products of PPARα-mediated thioesterase activity are upregulated in spaceflight mice.

<p><i>A</i>) Hepatic PPARα mRNA expression was quantified using qRT-PCR and normalized to 18S rRNA levels for both FLT mice and AEM controls. An unpaired t-test with Welch’s correction was used for comparison. PPARα targets include acyl-coA thioesterases, which act in different cellular compartments to mediate lipid metabolism. Mass spectrometry-based metabolomics analysis of liver compounds showed increased concentrations of products of <i>B</i>) ACOT2, <i>C</i>) ACOT1 and <i>D</i>) ACOT8 activity. Data (mean ± SEM) were plotted for <i>n</i> = 3–5 mice/group.</p

Spaceflight induces activation of PPARα pathways maintained by a feedback loop involving hepatic thioesterase activity and mediated by DHA.

<p>Elements of the space environment such as microgravity, oxidative stress and radiation may lead to activation of the PPARα-RXRα heterodimer by ω-3 fatty acids (including DHA), PGC-1α and retinoids from activated HSCs, increasing thioesterase activity. Hepatic steatosis, as well as synthesis of bile acids, ketone bodies and dicarboxylic acids, results from activation of downstream pathways. Fibrosis may also ensue from transformation of the activated HSCs. DHA and bile acids are ligands for FXR, which may be activated in a compensatory manner and help protect from HSC-induced remodeling of the ECM. PPRE, peroxisome proliferator response element.</p