Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes.

Implications of the Matrix Metalloproteinases, Their Tissue Inhibitors and Some Other Inflammatory Mediators Expression Levels in Children Obesity-Related Phenotypes

“…Opinions about TNF-alpha are divided, as Russell et al found that obese adolescent girls have an increased level of TNF-α receptors, which would enable TNF-α to bind more easily to its receptor and have a greater effect (such as IL-6 stimulation) without the need to increase the circulating TNF-α concentration [ 35 ]. TIMP-2 is ubiquitously, constitutively expressed protein that acts as a highly effective inhibitor of multiple MMPs including MMP-2 and MMP-9 [ 36 ]. TIMP-2 is also highly expressed in leukocytes [ 37 ].…”

“…MMP-12 is primarily secreted by activated macrophages and exhibits high specificity for elastin degradation. Recent observations suggest that that increased expression of MMP-12 by M2 macrophages in adipose tissue of obese subjects may be a compensatory mechanism to restrain adipose tissue expansion and insulin resistance [ 36 ]. Found here increased plasma leptin level and its strong positive correlation with liver inflammatory marker, GGTP (r = 0.964) suggest that leptin may induce pro-inflammatory reactions reflected by hepatocyte as an element of progressive, but still discrete inflammatory response in children with simple obesity.…”

Irisin: A Possible Marker of Adipose Tissue Dysfunction in Obesity

“…Obesity involves 170 million children (under the age of 18) and 650 million adults, with growing prevalence in low-and middle-income countries [52]. Obesity complications include type 2 diabetes mellitus (T2DM), thyroid diseases, hypertension, cancer, and depression, representing a worldwide concern both for the negative impact on the quality of life and for the associated elevated annual health-care costs [53].…”

“…Interestingly, irisin, as happens with MMPs, shows a different expression pattern depending on the study model, the stage of maturation, and the tissue location of adipose cells, and these aspects create many difficulties in gaining a full and complete understanding of its intrinsic clinical significance [40,41,52].…”

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…Zinc finger proteins can act as transcription factors that regulate HSCs activation, mitochondrial autophagy, the inflammatory response, and glucose-lipid metabolism, which influence MAFLD progression (Figure 1) [245][246][247][248][249]. In addition, zinc is a key component of matrix metalloproteinases (MMPs) that degrade the extracellular matrix, of which upregulated MMP14 and inactivated MMP11 are associated with hepatic steatosis, while upregulated MMP2 and MMP9 are associated with hepatic fibrosis and inflammation, respectively [250]. The coexistence of hepatic zinc deficiency and iron accumulation contributes to the development of hepatic fibrosis, which may be related to extracellular matrix remodeling and changes in lipid composition [251].…”