Protective hepatocyte signals restrain liver fibrosis in metabolic dysfunction–associated steatohepatitis
Marcella Steffani, Yana Geng, Utpal B. Pajvani, Robert F. Schwabe
Marcella Steffani, Yana Geng, Utpal B. Pajvani, Robert F. Schwabe
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Commentary

Protective hepatocyte signals restrain liver fibrosis in metabolic dysfunction–associated steatohepatitis

Abstract

Metabolic dysfunction–associated steatotic liver disease (MASLD) affects nearly 40% of the global adult population and may progress to metabolic dysfunction–associated steatohepatitis (MASH), and MASH-associated liver fibrosis and cirrhosis. Despite numerous studies unraveling the mechanism of hepatic fibrogenesis, there are still no approved antifibrotic therapies. The development of MASLD and liver fibrosis results from complex cell-cell interactions that often initiate within hepatocytes but remain incompletely understood. In this issue of the JCI, Yan and colleagues describe an ATF3/HES1/CEBPA/OPN pathway that links hepatocyte signals to fibrogenic activation of hepatic stellate cells and may provide new perspectives on therapeutic options for MASLD-induced liver fibrosis.

Authors

Marcella Steffani, Yana Geng, Utpal B. Pajvani, Robert F. Schwabe

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Figure 1

CEBPA confers antifibrotic effects via osteopontin suppression.

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CEBPA confers antifibrotic effects via osteopontin suppression. Activati...
Activation of ATF3 and HES1 in hepatocytes leads to a progressive suppression of CEBPA that tracks with MASH progression, triggering increased expression and secretion of OPN, encoded by SPP1, from hepatocytes. Hepatocyte-derived OPN induces the activation of HSCs and thereby contributes to liver fibrosis. Hepatocyte-specific silencing of ATF3, HES1, or SPP1, or activation of CEPBA expression via GalNAc-coupled siRNA or saRNA, respectively, could be used to inhibit fibrogenesis in MASH.