MDM2 deletion and its associated p53 activation in subcutaneous white adipose tissue induce hepatic fibrosis via galectin-3 in a mouse model.

BACKGROUND

White adipose tissue (WAT) communicates with distal metabolic organs and regulates their functions by secreting adipokines. Subcutaneous WAT (sWAT) is thought to be metabolically protective but prone to dysfunction with aging and obesity. Chronic activation of p53 is commonly observed in dysfunctional WAT at different anatomical locations in metabolic diseases. However, the impact of MDM2 deletion and its associated p53 activation in sWAT on adipokine profile and systemic metabolism is unknown.

METHODS AND

RESULTS

To investigate the effects of selective MDM2 deletion and its associated p53 activation in sWAT, we administered two independent adipotropic adeno-associated virus (AAV) vectors expressing Cre recombinase into the sWAT of Mdm2flox/flox mice to locally delete MDM2, a well-established negative regulator that targets p53 for degradation. Deletion of MDM2 resulted in sustained p53 activation, leading to senescence, apoptosis, and fibrosis in sWAT, but not in other fat depots or metabolic organs. sWAT dysfunction resulting from MDM2 deletion and its associated p53 activation had no obvious impact on systemic glucose or lipid metabolism, but progressively triggered hepatic inflammation, damage, and fibrosis. Proteomic analysis revealed that MDM2 deletion shifted the sWAT adipokine profile toward a more pro-inflammatory and pro-fibrotic state. Among the MDM2 deletion-induced sWAT-derived factors, galectin-3 acted as a major contributor to hepatic stellate cell activation and fibrogenesis via STAT3 signaling. At the molecular level, p53 bound to the Lgals3 promoter and upregulated its mRNA expression, thereby increasing galectin-3 secretion primarily in mature adipocytes.

CONCLUSION

Our findings reveal that sWAT dysfunction caused by MDM2 deletion and its associated p53 activation is sufficient to promote hepatic damage and fibrosis.