MMP-12 siRNA improves the homeostasis of the small intestine and metabolic dysfunction in high-fat diet feeding-induced obese mice

Song, Mingming; Zhang, Shiyao; Tao, Zixuan; Li, Jianning; Shi, Yujie; Xiong, Yifan; Zhang, Wenxiang; Liu, Chang; Chen, Siyu

doi:10.1016/j.biomaterials.2021.121183

Cited by 9 publications

(3 citation statements)

References 71 publications

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“…In liver injury, KC secrete MMPs to aid in fibrosis regression and tissue damage resolution 48 . In addition, MMP12 is pro-inflammatory and necessary for wound healing 49 . Recent studies suggest that the absence of MMP12 attenuates leaky gut and reduces immune cell infiltration and transmigration across the colonic epithelial barrier, leading to decreased inflammation and disease severity 49 , 50 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, MMP12 is pro-inflammatory and necessary for wound healing 49 . Recent studies suggest that the absence of MMP12 attenuates leaky gut and reduces immune cell infiltration and transmigration across the colonic epithelial barrier, leading to decreased inflammation and disease severity 49 , 50 . MMP12 is also necessary for fibrosis resolution, as inhibition of MMP12 increases elastin accumulation and fibrosis 51 .…”

Section: Discussionmentioning

confidence: 99%

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Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells

Lodge,

Scheidemantle,

Adams

et al. 2024

Sci Rep

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Over-consumption of fructose in adults and children has been linked to increased risk of non-alcoholic fatty liver disease (NAFLD). Recent studies have highlighted the effect of fructose on liver inflammation, fibrosis, and immune cell activation. However, little work summarizes the direct impact of fructose on macrophage infiltration, phenotype, and function within the liver. We demonstrate that chronic fructose diet decreased Kupffer cell populations while increasing transitioning monocytes. In addition, fructose increased fibrotic gene expression of collagen 1 alpha 1 (Col1a1) and tissue metallopeptidase inhibitor 1 (Timp1) as well as inflammatory gene expression of tumor necrosis factor alpha (Tnfa) and expression of transmembrane glycoprotein NMB (Gpnmb) in liver tissue compared to glucose and control diets. Single cell RNA sequencing (scRNAseq) revealed fructose elevated expression of matrix metallopeptidase 12 (Mmp12), interleukin 1 receptor antagonist (Il1rn), and radical S-adenosyl methionine domain (Rsad2) in liver and hepatic macrophages. In vitro studies using IMKC and J774.1 cells demonstrated decreased viability when exposed to fructose. Additionally, fructose increased Gpnmb, Tnfa, Mmp12, Il1rn, and Rsad2 in unpolarized IMKC. By mass spectrometry, C13 fructose tracing detected fructose metabolites in glycolysis and the pentose phosphate pathway (PPP). Inhibition of the PPP further increased fructose induced Il6, Gpnmb, Mmp12, Il1rn, and Rsad2 in nonpolarized IMKC. Taken together, fructose decreases cell viability while upregulating resolution and anti-inflammatory associated genes in Kupffer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells

Lodge,

Scheidemantle,

Adams

et al. 2024

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Accordingly, the enzyme has been proposed as a potential target for a variety of inflammatory conditions, including respiratory diseases [ 16 ], granulomas [ 17 , 18 ], different types of cancer [ 19 – 21 ], and neurological and musculoskeletal disorders [ 22 , 23 ]. Knockdown of MMP12 in the small intestine ameliorated high-fat diet-induced metabolic disturbances and intestinal homeostasis in mice [ 24 ]. Moreover, the enzyme also plays a deleterious role in obesity-induced chronic kidney disease by aggravating glomerular fibrogenesis, oxidative stress, and inflammation [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

Amor,

Bianco,

Buerger

et al. 2023

Cardiovasc Diabetol

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Background Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear. Methods We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16–20 weeks. Results DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs. Conclusion We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.

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siRNA/CS‐PLGA Nanoparticle System Targeting Knockdown Intestinal SOAT2 Reduced Intestinal Lipid Uptake and Alleviated Obesity

Liang,

Shao,

et al. 2024

Advanced Science

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Effective inhibition of intestinal lipid uptake is an efficient strategy for the treatment of disorders related to lipid metabolism. Sterol O‐acyltransferase 2 (SOAT2) is responsible for the esterification of free cholesterol and fatty acids into cholesteryl esters. We found that intestine‐specific SOAT2 knockout (Soat2I‐KO) mice was capable to prevent the development of dietary induced obesity due to reduced intestinal lipid absorption. Soat2 siRNA/CS‐PLGA nanoparticle system was constructed to enable intestinal delivery and inhibition of Soat2. This nanoparticle system was composed of PLGA‐block‐PEG and chitosan specifically delivering Soat2 siRNAs into small intestines in mice, effectively inhibit intestinal lipid uptake and resolving obesity. In revealing the underlying mechanism by which intestinal SOAT2 regulating fatty acid uptake, enhanced CD36 ubiquitination degradation was found in enterocytes upon SOAT2 inhibition. Insufficient free cholesterol esterification promoted endoplasmic reticulum stress and recruitment of E3 ligase RNF5 to activate CD36 ubiquitination in SOAT2 knockdown enterocytes. This work demonstrates a potential modulatory function of intestinal SOAT2 on lipid uptake highlighting the therapeutic effect on obesity by targeting intestinal SOAT2, exhibiting promising translational relevance in the siRNA therapeutic–based treatment for obesity.

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MMP-12 siRNA improves the homeostasis of the small intestine and metabolic dysfunction in high-fat diet feeding-induced obese mice

Cited by 9 publications

References 71 publications

Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells

Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells

Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice

siRNA/CS‐PLGA Nanoparticle System Targeting Knockdown Intestinal SOAT2 Reduced Intestinal Lipid Uptake and Alleviated Obesity

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