Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD.

Autor:	Johanns M; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Haas JT; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Raverdy V; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1190-EGID, F-59000 Lille, France., Vandel J; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Chevalier-Dubois J; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Guille L; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Derudas B; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Legendre B; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1190-EGID, F-59000 Lille, France., Caiazzo R; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1190-EGID, F-59000 Lille, France., Verkindt H; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1190-EGID, F-59000 Lille, France., Gnemmi V; Univ. Lille, Inserm, CHU Lille, UMR 1172, Lille, France., Leteurtre E; Univ. Lille, Inserm, CHU Lille, UMR 1172, Lille, France., Derhourhi M; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR 1283/8199-EGID, F-59000 Lille, France., Bonnefond A; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR 1283/8199-EGID, F-59000 Lille, France.; Department of Metabolism, Imperial College London; London, United Kingdom., Froguel P; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR 1283/8199-EGID, F-59000 Lille, France.; Department of Metabolism, Imperial College London; London, United Kingdom., Eeckhoute J; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Lassailly G; Univ. Lille, Inserm, CHU Lille, UMR 995-LIRIC, Lille, France., Mathurin P; Univ. Lille, Inserm, CHU Lille, UMR 995-LIRIC, Lille, France., Pattou F; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1190-EGID, F-59000 Lille, France., Staels B; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France., Lefebvre P; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR1011-EGID, F-59000 Lille, France.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2023 Oct 27; Vol. 6 (1), pp. 100948. Date of Electronic Publication: 2023 Oct 27 (Print Publication: 2024).
DOI:	10.1016/j.jhepr.2023.100948
Abstrakt:	Background & 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 disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-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: Herein, we provide 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, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ 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. Impact and Implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases. Competing Interests: The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2023 The Authors.)
Databáze:	MEDLINE
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