Loss of MMP12 in LAL-D and cardiometabolic disease

Lysosomal acid lipase deficiency is a rare metabolic disorder, eventually causing early death of critically ill patients due to malabsorption, liver failure, and atherosclerosis. In contrast, cardiometabolic diseases, such as type 2 diabetes mellitus and cardiovascular diseases, are leading causes of global mortality and direct consequences of the obesity epidemic. Current efforts in the field of biomedical research strive to design efficient therapeutic strategies capable of treating obesity-associated cardiometabolic diseases. Previous studies and our preliminary data identified matrix metalloproteinase 12 (MMP12) as a potential molecular target for the treatment of these diseases. The abundance of MMP12 has been related to the development of a wide spectrum of pathological conditions. Our research aims focus on understanding the role of MMP12 in the above mentioned diseases, address the underlying mechanisms, investigate associations between MMP12 and metabolic disorders in human tissues, investigate the effects of MMP12 in cellular dysfunction, and elucidate the consequences of MMP12 depletion in disease using an immunotherapeutic approach. Thus, this proposal will evaluate the potential of MMP12 as a target for lysosomal acid lipase deficiency and/or cardiometabolic diseases, which might eventually represent a novel therapeutic approach for the treatment of these diseases.

MMP12 is a protein secreted by macrophages. It has been proposed as a marker of poor prognosis and an attractive molecular target for drugs in various inflammatory and metabolic diseases. MMP12 has been identified as a massively upregulated pro-inflammatory factor in the lungs of LAL-deficient (LAL-D) mice. In humans, LAL-D is a rare metabolic disorder that causes liver damage, dyslipidemia, and atherosclerosis. Since current therapies have limitations, such as undesirable side effects or exorbitant costs, novel players and new therapeutic approaches are urgently needed. The results of this project showed that deleting the pro-inflammatory protein MMP12 in LAL-D helped to reduce inflammation in the liver. This was accompanied by reduced abundance of inflammatory immune cell (neutrophil) markers but unchanged number of macrophages. The findings indicate that MMP12 affects the survival of neutrophils rather than their production. Deletion of MMP12 helped to improve lymphocyte function, but the exact mechanism of action is not yet known. We conclude that MMP12 contributes to immune system dysfunction in LAL-D but is not a viable target for treatment. Elevated MMP12 concentrations were also found in patients with cardiometabolic diseases, such as diabetes and cardiovascular diseases, indicating a pathological role of MMP12 in these diseases as well. Obesity and overweight are becoming more common worldwide, which is causing more people to develop these diseases. To better understand the potential role of MMP12 in these diseases, we studied MMP12 in a cardiometabolic mouse model that develops obesity-related problems. We observed that cardiometabolic mice without MMP12 had less lipids in the blood, smaller atherosclerotic plaques and less collagen content in their aortas and aortic valves. This result suggests that the presence of MMP12 causes atherosclerosis. Functional studies also showed that the aortic rings worked better in these mice. Proteomics analyses of different metabolic tissues from these mice led to the identification of downregulated proteins related to inflammation, insulin resistance, and atherosclerosis. These proteins might be therapeutically targeted in the future for mitigating cardiovascular complications associated with diabetes. In addition, we saw that mice lacking MMP12 had better metabolic function. This might be because their brown fat was more active, produced more heat, and had less fat. We also identified some factors that might be involved in the crosstalk between brown fat and the liver in cardiometabolic diseases. These factors might be released from the brown fat and taken up by the liver when the ambient temperature is reduced. Genetic variations in the genes encoding these factors have been linked to cardiometabolic-related phenotypes and traits in humans. We conclude that deleting MMP12 may improve atherosclerosis and chronic inflammation and activate brown fat. Thus, targeting MMP12 might help fighting cardiometabolic diseases.