Effects of long‐term simulated microgravity on liver metabolism in rhesus macaques

Abstract

The liver is an essential multifunctional organ and constantly communicates with nearly all the tissues in the body. Spaceflight or simulated microgravity has a significant impact on the livers of rodent models, including lipid accumulation and inflammatory cell infiltration. Whether similar liver lipotoxicity could occur in humans is not known, even though altered circulating cholesterol profile has been reported in astronauts. Using a 42‐day head‐down bed rest (HDBR) model in rhesus macaques, the present study investigated whether simulated microgravity alters the liver of non‐human primates at the transcriptome and metabolome levels. Its association with stress and intestinal changes was also explored. Compared to the controls, the HDBR monkeys showed mild liver injury, elevated ANGPTL3 level in the plasma, and accumulation of fat vacuoles and inflammatory cells in the liver. Altered transcriptome signatures with up‐regulation of genes in lipid metabolisms and down‐regulation of genes in innate immune defense were also found in HDBR group‐derived liver samples. The metabolic profiling of the liver revealed mildly disturbed fatty acid metabolism in the liver of HDBR monkeys. The intestinal dysbiosis, its associated endotoxemia and changes in the composition of bile acids, and elevated stress hormone in HDBR monkeys may contribute to the altered lipid metabolisms in the liver. These data indicate that liver metabolic functions and gut‐liver axis should be closely monitored in prolonged spaceflight to facilitate strategy design to improve and maintain metabolic homeostasis.

Melatonin ameliorates simulated‐microgravity‐induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes

“…A previous study on the effect of long‐term SMG on lipid metabolism in rhesus macaque livers 19 led us to investigate whether SMG exposure would target fat accretion in hepatocytes. Using Oil Red O and Nile red to stain neutral lipids, we found that compared to NG, cells treated with SMG for six days showed more Oil Red O puncta, suggesting more LDs (Figures 2A and S2A).…”

Vascular smooth muscle cell‐specific miRNA‐214 deficiency alleviates simulated microgravity‐induced vascular remodeling

“…5,9,23 Hindlimb unloading is widely utilized to study the effects of microgravity in mice or rats, and head-down tilt bed rest model for non-human primate-rhesus monkeys or human volunteers is also a classical ground-based model of microgravity. [24][25][26][27][28][29][30] Previous studies have found forebody artery remodeling during microgravity. Simulated microgravity experienced by hindlimb unloading rats induced such thoracic aortic structural and functional changes as increased thoracic aortic stiffness is due to both increased aortic collagen content and enzyme cross-linking activity.…”

“…The mechanism underlying this phenomenon remains unclear, but vascular remodeling, such as common carotid artery and aortic stiffness, may be an important contributor to postflight cardiovascular deconditioning 5,9,23 . Hindlimb unloading is widely utilized to study the effects of microgravity in mice or rats, and head‐down tilt bed rest model for non‐human primate‐rhesus monkeys or human volunteers is also a classical ground‐based model of microgravity 24–30 . Previous studies have found forebody artery remodeling during microgravity.…”

Choroidal circulation disturbance is an initial factor in outer retinal degeneration in rats under simulated weightlessness

“…Presently, research methods for ground simulation of weightlessness mainly include the head-down-tilt bed rest for humans and the tail suspension experiment for animals . The effects of the spaceflight environment on the cardiovascular, musculoskeletal, immunological, neurological, renal, metabolic, reproductive, and visual systems have been confirmed by simulated microgravity (Wise et al, 2005;Hu et al, 2017;Horie et al, 2018;Li et al, 2022;Zong et al, 2022). Animal earth-based analogs are widely used to investigate disorders that might occur during space missions.…”