Metabolic Associated Fatty Liver Disease (MAFLD) is a chronic liver disease closely related to metabolic dysfunction which is characterized by excessive fat deposition in the liver and accompanied by metabolic disorders such as insulin resistance and dyslipidemia. Zebrafish, with its unique biological advantages, serves as an excellent model for studying MAFLD pathology.

Suppressor of cytokine signaling 8 (SOCS8), a key regulatory factor in cytokine signaling, inhibits the Janus Tyrosine Kinase/Signal Transducers and Activators of Transcription pathway, regulating immune responses and metabolic balance. It has been identified as a fish-specific gene controlling metabolic inflammation.

In a study published in Water Biology and Security, a research group led by Prof. XIA Xiaoqin at the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences developed SOCS8 knockout zebrafish that can effectively model MAFLD progression. The knockout mutants at different ages successfully simulated the staged development of immune and metabolic disorders associated with MAFLD in both intestine and liver.

Researchers conducted weighted co-expression analysis of the transcriptome and immune cell infiltration studies. One-month-old homozygous mutants exhibited increased M2 macrophage regulation and hepatotoxic free fatty acid accumulation, corresponding to simple fatty liver disease. In three-month-old mutants, sterol metabolism dysfunction indicated endoplasmic reticulum stress, while DNA repair pathway activation suggested fibrotic progression, matching non-alcoholic steatohepatitis characteristics.

Besides, in intestinal tissues of SOCS8-deficient zebrafish, researchers observed immune responses and microbiota changes. At one month, they detected enhanced mucus secretion, upregulated IgA production pathways, and activated O-mannose biosynthesis. They also found strengthened tissue repair mechanisms mediated by Interleukin-13 and arachidonic acid metabolism. Microbiota analysis revealed increased Prevotella and decreased Veillonella. 

By three months, opportunistic bacteria proliferated excessively, exacerbating gut barrier damage and driving liver lipid toxicity via the gut-liver axis. Single-cell sequencing showed reduced neutrophils and macrophages but elevated T lymphocyte/Natural Killer cells in three-month-old mutants, indicating chronic lymphocyte-mediated inflammation consistent with MAFLD intestinal pathology.

This study establishes SOCS8 knockout zebrafish as a novel model for MAFLD, and revealed how metabolic inflammation progresses through gut-liver interactions. It provides insights into MAFLD stages and highlights potential therapeutic targets for metabolic disorders.