Metabolic Associated Fatty Liver Disease (MAFLD) is a chronic liver disease closely related to metabolic dysfunction, characterized by excessive fat deposition in the liver (hepatic steatosis) and accompanied by metabolic disorders such as insulin resistance, obesity, or 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 (JAK/STAT) pathway,  thereby regulating immune responses and metabolic balance. As a fish-specific gene controlling metabolic inflammation, SOCS8 offers critical insights into MAFLD mechanisms. However, its role in MAFLD progression through the gut-liver axis remained unclear.

To address this, the Research Group on Fish Functional Genomics at the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences, led by Prof. XIA Xiaoqin, developed SOCS8 knockout zebrafish that effectively modeled MAFLD progression. These knockout mutants at different ages successfully simulated the staged development of immune and metabolic disorders associated with MAFLD in both intestine and liver. The study was published in Water Biology and Security.

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

In intestinal tissues of SOCS8-deficient zebrafish, researchers observed immune responses and microbiota changes. At one month, they detected enhanced mucus secretion (increased goblet cells), upregulated IgA production pathways, and activated O-mannose biosynthesis. They also found strengthened tissue repair mechanisms mediated by Interleukin-13 (IL13) and arachidonic acid metabolism. Microbiota analysis revealed increased Prevotella (linked to elevated glucose metabolism) and decreased Veillonella (associated with intestinal cavity emptying). By three months, opportunistic bacteria (e.g., Proteobacteria) proliferated excessively, exacerbating gut barrier damage and driving liver lipid toxicity via the gut-liver axis.

Single-cell sequencing (MGI DNBSEQ-T7) further showed reduced neutrophils and macrophages but elevated T lymphocyte/Natural Killer (T/NK) 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, revealing how metabolic inflammation progresses through gut-liver interactions. The findings provide mechanistic insights into MAFLD stages and highlight potential therapeutic targets for metabolic disorders.

(Online 28 April 2025)

(Editor: MA Yun)