Multi-omics analysis of multiple missions to space reveal a theme of lipid dysregulation in mouse liver

Afshin Beheshti,Gary Hardiman,Homer Fogle,Sylvain V Costes,Deanne Taylor,Amanda M Saravia-Butler,Hossein Fazelinia,Valery Boyko,Kaushik Chakravarty,Willian A Da Silveira,Jonathan M Galazka,San-Huei Lai Polo

doi:10.1038/s41598-019-55869-2

Abstract

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models. Mouse studies performed on the Space Shuttle showed disruption of lipid metabolism in liver. However, given that these animals were not sacrificed on-orbit and instead returned live to earth, it is unclear if these disruptions were solely induced by space stressors (e.g. microgravity, space radiation) or in part explained by the stress of return to Earth. In this work we analyzed three liver datasets from two different strains of mice (C57BL/6 (Jackson) & BALB/c (Taconic)) flown aboard the International Space Station (ISS). Notably, these animals were sacrificed on-orbit and exposed to varying spaceflight durations (i.e. 21, 37, and 42 days vs 13 days for the Shuttle mice). Oil Red O (ORO) staining showed abnormal lipid accumulation in all space-flown mice compared to ground controls regardless of strain or exposure duration. Similarly, transcriptomic analysis by RNA-sequencing revealed several pathways that were affected in both strains related to increased lipid metabolism, fatty acid metabolism, lipid and fatty acid processing, lipid catabolic processing, and lipid localization. In addition, key upstream regulators were predicted to be commonly regulated across all conditions including Glucagon (GCG) and Insulin (INS). Moreover, quantitative proteomic analysis showed that a number of lipid related proteins were changed in the livers during spaceflight. Taken together, these data indicate that activation of lipotoxic pathways are the result of space stressors alone and this activation occurs in various genetic backgrounds during spaceflight exposures of weeks to months. If similar responses occur in humans, a prolonged change of these pathways may result in the development of liver disease and should be investigated further.

Highlights

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models
We have utilized mice liver samples from both the Rodent Research 1 (RR-1) and Rodent Research 3 (RR-3) missions to further confirm whether increases in lipids in the liver is the result of spaceflight alone
A subset of the metabolic pathways and molecular factors seem consistent with Non-alcoholic fatty liver disease (NAFLD), a www.nature.com/scientificreports multi-factorial metabolic disease that upon progression could lead to non-alcoholic steatohepatitis (NASH) and irreversible liver fibrosis[13,14,27]

Summary

Introduction

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models. One study from Jonscher et al has reported findings in mice flown for 13 days aboard the Space Transportation System (STS)−135 to have liver damage through accumulation of hepatic lipids droplets, elevated triglyceride levels, and loss of retinoids from the hepatic stellate cells (HSC) lipid droplets[9] These results were correlated with the activation of peroxisome proliferator-activated receptor alpha (PPARα). Several proteomic studies on the liver related to NAFLD have revealed key pathways being regulated in the liver which include cell cycle, glucose metabolism, autophagy, ketogenesis, and fatty acid transport that corresponds with what is being observed with the spaceflight samples[17,18]

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Conclusion