Loss of liver function in chronic liver disease: An identity crisis

• Published in: Journal of hepatology 2023-02, Vol.78 (2), p.401-414
• Main Authors: Berasain, Carmen, Arechederra, Maria, Argemí, Josepmaria, Fernández-Barrena, Maite G., Avila, Matías A.
• Format: Article
• Language: English
• Subjects: Chronic liver disease; hepatocellular differentiation; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Hepatocytes - metabolism; Humans; Identity Crisis; Liver - metabolism; Liver Diseases - metabolism; molecular therapies; mRNA splicing factors; transcription factors; Transcription Factors - metabolism; transcriptional reprogramming
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2022.09.001

Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.