Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD
Abstract
Background and aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) progression in rodent models. We therefore investigated whether time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers.
Methods: Liver biopsies, collected within an 8 hour-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers.
Results: We provide here a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intra-cellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFA and PPARG signaling were predicted as important contributors to altered rhythmicity.
Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained.
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