Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation.

Area of Science:

• Hepatology
• Molecular Biology
• Translational Medicine

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma are significant clinical issues.
• Chronic endoplasmic reticulum (ER) stress from high-fat diets (HFD) drives MASH pathogenesis through inflammation and dysfunction.
• Posttranscriptional regulation in hepatocyte adaptation to ER stress is not well understood.

Purpose of the Study:

• To define the posttranscriptional landscape in response to chronic HFD exposure.
• To investigate the role of ER stress in modulating gene expression posttranscriptionally.
• To identify adaptive mechanisms in hepatocytes under metabolic stress.

Main Methods:

• Integrative analysis of transcriptomics, ribosome profiling, and polyadenylation.
• Hepatocyte-specific knockout of ER stress translational regulators.
• Cis-regulatory mapping of mRNA 3' untranslated regions (UTRs).

Main Results:

• Approximately 70% of HFD-induced gene expression changes occur at the translational level.
• A subset of mRNAs with short poly(A) tails are activated by poly(A) tail elongation under HFD.
• These activated transcripts are linked to cell cycle, immune response, fibrosis, and correlate with MASH severity in mice and humans.

Conclusions:

• Posttranscriptional control, particularly translational regulation via poly(A) tail dynamics, is crucial for MASH pathogenesis.
• Adaptive responses involving specific mRNA subsets are critical for mitigating liver damage.
• Disruption of this adaptive translational control exacerbates liver injury and tumor development in MASH models.