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Updated: Jan 15, 2026
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
Macrophage Plg-RKT expression promotes diet-induced obesity and metabolic dysfunction-associated steatotic liver
Lindsey A Miles1, Hongdong Bai2, Sagarika Chakrabarty3
1Department of Cell and Molecular Biology, Scripps Research, La Jolla, California, USA.
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.
Insights
Macrophage plasminogen receptor KT (Plg-RKT) is critical for high-fat diet-induced obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Blocking Plg-RKT in macrophages protects against obesity and MASLD, highlighting its therapeutic potential.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Diseases
Background:
- Plasminogen receptor KT (Plg-RKT) is a transmembrane receptor that enhances plasminogen activation.
- Plg-RKT localizes plasmin activity to the cell surface.
Purpose of the Study:
- To investigate the role of Plg-RKT in high-fat diet (HFD)-induced obesity.
- To determine the cell-specific function of Plg-RKT in metabolic dysfunction-associated steatotic liver disease (MASLD).
Main Methods:
- Mice with macrophage-specific (mPlg-RKT-/-) or hepatocyte-specific (hPlg-RKT-/-) Plg-RKT deficiency were fed an HFD.
- Evaluated glucose homeostasis, hepatic lipogenesis, fatty acid oxidation, adipose macrophage phenotypes, and inflammation.
- Performed RNA sequencing on liver tissue to identify gene expression changes.
Main Results:
- Macrophage Plg-RKT deficiency protected mice from HFD-induced obesity, MASLD, and liver dysfunction.
- mPlg-RKT-/- mice showed reduced liver fat, improved glucose homeostasis, and altered macrophage polarization towards an anti-inflammatory M2 phenotype.
- Hepatocyte-specific deficiency (hPlg-RKT-/-) did not confer protection, indicating a macrophage-specific role.
- Mechanistic studies revealed reduced Akt activation, decreased fatty acid synthase, and activated PPARα pathway in mPlg-RKT-/- mice.
Conclusions:
- Macrophage Plg-RKT signaling is a critical driver in the pathogenesis of obesity and MASLD.
- Targeting macrophage Plg-RKT may represent a therapeutic strategy for metabolic disorders.
