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Disrupting “talk” amongst liver cells yields therapeutic targets for nonalcoholic fatty liver disease

Researchers “listening in” on how liver cells chemically “talk” amongst themselves has uncovered a host of new targets for therapies against a common and advanced stage of nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease and its more severe form of nonalcoholic steatohepatitis (NASH) are common in both adults and children in the United States and around the world. No approved therapy exists for NASH, which is among the leading causes of liver transplantation and liver cancer. NASH is marked not only by excess fat accumulation in the liver, but also liver inflammation and fibrosis, or scar tissue formation, mostly driven by overactivity of a type of liver cell called a hepatic stellate cell. Mechanisms driving this activation, or how to halt or even reverse it, are not fully understood.

One potential way hepatic stellate cells (HSCs) can become activated is by “talking” amongst themselves and with other cells nearby. As part of this “conversation”, the activated HSCs also send their own signals creating self-perpetuating feedback loops or circuits. Scientists wondered if, by zeroing in on these signaling circuits, they could interrupt them, breaking the cycle that keeps the liver cells activated and causes disease. They used a new technology capable of analyzing genetic products of single cells—simultaneously for millions of cells—to provide a unique signature for each cell based on its signaling components. Examining liver samples from women and men with NASH and from male and female mice with diet- and chemical-induced NASH, they identified some common circuits, composed of 68 unique proteins and their receptors, that emerge in the activated liver cells only during the late stage of NASH. The researchers then visualized these circuits using technologies that map contacts among neighboring cells. In this way, they showed the liver cells physically reaching out and becoming increasingly well-connected to each other over the disease course, enabling exchange of short-range signals to sustain their collective activation and drive disease progression. To explore the therapeutic applications of this finding, the team blocked one of the protein-receptor signaling circuits, in cultured human liver cells and in the animal model and found that blocking this circuit led to inactivation of disease-causing liver cells.

In this study, the research team applied cutting-edge technologies in single-cell sequencing and imaging to uncover new insights into how to interrupt the “vicious cycle” of cellular signals underlying fibrosis in late-stage nonalcoholic fatty liver disease. This work offers a basis for developing what could be the first dedicated therapy for this common and severe form of liver disease.

Wang S, Li K, Pickholz E,…Friedman SL. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med 15: eadd3949, 2023.

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