Macrophage Plg-RKT expression promotes diet-induced obesity and metabolic dysfunction-associated steatotic liver disease.

BACKGROUND

Plg-RKT is a transmembrane plasminogen receptor that enhances the activation of plasminogen to plasmin and localizes proteolytic activity of plasmin on the cell surface.

OBJECTIVES

We investigated the role of Plg-RKT in high-fat diet (HFD)-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).

METHODS

Mice deficient in Plg-RKT in macrophages (mPlg-RKT-/-) or hepatocytes (hPlg-RKT-/-) and control mice (Plg-RKTflox/flox) were fed a HFD to determine the cell-specific role of this receptor in obesity and MASLD. Glucose homeostasis, hepatic lipogenesis, fatty acid oxidation pathways, adipose macrophage phenotypes, and inflammation were analyzed. RNA sequencing analysis of liver was performed to identify differentially expressed genes and functional pathways impacted by the loss of myeloid Plg-RKT.

RESULTS

Plg-RKT levels were significantly elevated in the liver of HFD-fed mice with MASLD. HFD-fed mPlg-RKT-/- mice were protected from obesity, MASLD, and liver dysfunction. mPlg-RKT-/- mice exhibited reduced liver fat, lower plasma alanine aminotransferase levels, and improved glucose homeostasis. In contrast, HFD-fed hPlg-RKT-/- mice were not protected from obesity and MASLD. Mechanistically, mPlg-RKT deficiency reduced hepatic Akt activation, lowered fatty acid synthase expression, and activated the PPARα fatty acid oxidation pathway. In adipose tissue, mPlg-RKT deficiency shifted macrophage polarization from proinflammatory M1-like to anti-inflammatory M2-like, enhancing insulin sensitivity, decreasing lipolysis, and lowering plasma free fatty acids available for liver uptake. RNA sequencing revealed significant gene expression changes in lipid metabolism, fibrosis, and inflammation.

CONCLUSION

These findings underscore the critical role of macrophage Plg-RKT signaling in the pathogenesis of obesity and MASLD.