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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\u2010day head\u2010down bed rest (HDBR) model in rhesus macaques, the present study investigated whether simulated microgravity alters the liver of non\u2010human 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\u2010regulation of genes in lipid metabolisms and down\u2010regulation of genes in innate immune defense were also found in HDBR group\u2010derived liver samples. 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