A deficiency in the essential nutrients methionine and choline (MCD) leads to a profound reprogramming of gene expression in liver cells. These changes reflect key molecular features of metabolically dysfunctional steatohepatitis (MASH) in humans. This is shown by a new study from the University of Texas Health Science Center San Antonio, published in the journal Journal of Lipid Research.
In cell culture models, the scientists led by Xiaoli Sun investigated four central liver cell types – hepatocytes (HepG2), endothelial cells, macrophages, and hepatic stellate cells. Under MCD conditions, all cell types showed a common transcriptional response: strong activation of inflammatory and stress signaling pathways (including interferon, TNF-NFκB, and IL6-JAK-STAT3 signals) and a clear suppression of metabolic and cell cycle-associated programs.
Additionally, cell type-specific changes occurred that may contribute to MASH pathogenesis: hepatocytes enhanced detoxification and oxidative stress responses while inhibiting sterol and lipid biosynthesis; endothelial cells showed increased inflammation and vascular remodeling; macrophages activated inflammatory and phagocytosis pathways while repressing lipid and SAM metabolism; stellate cells switched from a quiescent, lipid-storing state to a pro-fibrotic, inflammation-promoting state.
By comparing with single-nucleus RNA sequencing data from human MASH livers, the team was able to show that the MCD-induced transcriptional programs replicate essential pathophysiological features of the human disease: increased inflammation, enhanced hepatocyte death, disrupted redox balance, altered metabolic homeostasis, and activation of stellate cells.
The study thus not only provides mechanistic insights into how nutrient deficiency drives MASH development, but also supports the relevance of MCD-based models for researching the disease. At the same time, it underscores the importance of a balanced supply of methionine and choline for maintaining liver homeostasis.
In the long term, the findings could help to develop more targeted therapeutic strategies against MASH that aim at cell type-specific transcriptional changes.
