ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

Niu, Dun; Li, Lanfang; Xie, Zhizhong

doi:10.1177/10742484211023639

Cited by 5 publications

(4 citation statements)

References 100 publications

(138 reference statements)

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“…In contrast with that of ClC-3 −/− mice consuming a high-fat diet ( Ma et al, 2019 ), there were no significant differences in blood lipids between ClC-3 −/− and ClC-3 +/+ mice with a normal diet at the age of 12 weeks; intraperitoneal glucose tolerance test demonstrated that ClC-3 deletion delayed the response to blood glucose increasing and enhanced the efficiency of lowering blood glucose once started ( Figure 2 ). ClC-3 −/− mice had a partial impairment of glucose tolerance in the condition of ad libitum self-feeding normal diet, which may be associated with the inhibition of insulin secretion by ClC-3 knocking out ( Barg et al, 2001 ; Deriy et al, 2009 ; Li et al, 2009 ; Niu et al, 2021 ). This finding appeared to be inconsistent with the improvement of glucose tolerance impairment in ClC-3 −/− mice with obesity or diabetes ( Huang et al, 2014 ; Ma et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…ClC-3 chloride channels are widely expressed in most mammalian cells and are primarily localized on cell and organelle membranes. Regarding the important roles in the vasculature’s pathological changes, ClC-3 was considered a promising therapeutic target for cardiovascular diseases (CVDs) ( Duan, 2011 ; Du and Guan, 2015 ; Niu et al, 2021 ). It is well known that diabetes, dyslipidemia, and hypertension are CVDs’ most common risk factors.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic and transcriptomic alterations in the ClC-3-deficient mice consuming a normal diet

Jing

Zhang

Wen

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Metabolic disorders are an important health concern that threatens life and burdens society severely. ClC-3 is a member of the chloride voltage-gated channel family, and ClC-3 deletion improved the phenotypes of dysglycemic metabolism and the impairment of insulin sensitivity. However, the effects of a healthy diet on transcriptome and epigenetics in ClC-3−/− mice were not explained in detail.Methods: Here, we performed transcriptome sequencing and Reduced Representation Bisulfite Sequencing for the liver of 3 weeks old WT and ClC-3−/− mice consuming a normal diet to insight into the epigenetic and transcriptomic alterations of ClC-3 deficient mice.Results: In the present study, we found that ClC-3−/− mice that were younger than 8 weeks old had smaller bodies compared to ClC-3+/+ mice with ad libitum self-feeding normal diet, and ClC-3−/− mice that were older than 10 weeks old had a similar body weight. Except for the spleen, lung, and kidney, the average weight of the heart, liver, and brain in ClC-3−/− mice was lower than that in ClC-3+/+ mice. TG, TC, HDL, and LDL in fasting ClC-3−/− mice were not significantly different from those in ClC-3+/+ mice. Fasting blood glucose in ClC-3−/− mice was lower than that in ClC-3+/+ mice; the glucose tolerance test indicated the response to blood glucose increasing for ClC-3−/− mice was torpid, but the efficiency of lowering blood glucose was much higher once started. Transcriptomic sequencing and reduced representation bisulfite sequencing for the liver of unweaned mice indicated that ClC-3 deletion significantly changed transcriptional expression and DNA methylation levels of glucose metabolism-related genes. A total of 92 genes were intersected between DEGs and DMRs-targeted genes, of which Nos3, Pik3r1, Socs1, and Acly were gathered in type II diabetes mellitus, insulin resistance, and metabolic pathways. Moreover, Pik3r1 and Acly expressions were obviously correlated with DNA methylation levels, not Nos3 and Socs1. However, the transcriptional levels of these four genes were not different between ClC-3−/− and ClC-3+/+ mice at the age of 12 weeks.Discussion: ClC-3 influenced the methylated modification to regulate glucose metabolism, of which the gene expressions could be driven to change again by a personalized diet-style intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic and transcriptomic alterations in the ClC-3-deficient mice consuming a normal diet

Jing

Zhang

Wen

et al. 2023

Front. Cell Dev. Biol.

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“…HDL has been shown to protect against LDL oxidation, thereby preventing the generation of proinflammatory oxidized lipids ( 23 ). Notably, Clcn3 deficiency prevents atherosclerotic lesion development in ApoE −/− mice ( 24 ). The results depicted in Figure 3 proved that the knockout of Clcn3 caused a decrease in LDL levels among mice fed with HFD.…”

Section: Discussionmentioning

confidence: 99%

Clcn3 deficiency ameliorates high-fat diet-induced obesity and improves metabolism in mice

Duan,

Li,

Cui

et al. 2024

Front. Nutr.

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ObjectiveObesity is defined as excess body fat and is a current health epidemic associated with increased risk for type 2 diabetes and cardiovascular disease. The ClC-3 chloride channel/antiporter, encoded by the Clcn3, is associated with some diseases, like carcinoma, nervous system diseases, and metabolic diseases. To verify the relationship between the Clcn3 and weight including metabolic changes, searching for a new target for metabolic therapy of obesity, we designed the experiment.MethodsThe mice were divided into 4 different groups: Clcn3+/+ mice + high-fat diet (HFD), Clcn3−/− mice + HFD, Clcn3+/+ mice + normal diet (ND), Clcn3−/− mice + ND, and fed for 16 weeks. After the glucose tolerance test and insulin tolerance test, peripheral blood and adipose tissues were collected. Moreover, we performed transcriptome sequencing for the epididymal white adipose tissue from Clcn3+/+ and Clcn3−/− mice with the high-fat diet. Western blotting verified the changes in protein levels of relevant metabolic genes.ResultsWe found that the Clcn3−/− mice had lower body weight and visceral fat, refining glucose and lipid metabolism in HFD-induced mice, but had no effect in normal diet mice. RNA-seq and Western blotting indicated that Clcn3 deficiency may inhibit obesity through the AMPK-UCP1 axis.ConclusionModulation of Clcn3 may provide an appealing therapeutic target for obesity and associated metabolic syndrome.

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“…As one of the most abundant anions in organisms, chloride ions regulate a very wide range of physiological activities. The ClC-3 chloride channels, a kind of voltage-gated anion channel, participates in ion homeostasis, the regulation of cell volume, acidification of the internal environment, proliferation, apoptosis and many other processes in biological systems [ 4 , 5 ]. Recent studies have found that ClC-3 chloride channels are closely related to bone metabolism.…”

Section: Introductionmentioning

confidence: 99%

The role of the Smad2/3/4 signaling pathway in osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells

Wang

et al. 2022

J Orthop Surg Res

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Background ClC-3 chloride channels promote osteogenic differentiation. Transforming growth factor-β1 (TGF-β1) and its receptors are closely related to ClC-3 chloride channels, and canonical TGF-β1 signaling is largely mediated by Smad proteins. The current study aimed to explore the role of the Smad2/3/4 signaling pathway in the mechanism by which ClC-3 chloride channels regulate osteogenic differentiation in osteoblasts. Methods First, real-time PCR and western blotting were used to detect the expression of Smad and mitogen-activated protein kinase (MAPK) proteins in response to ClC-3 chloride channels. Second, immunocytochemistry, coimmunoprecipitation (Co-IP) and immunofluorescence analyses were conducted to assess formation of the Smad2/3/4 complex and its translocation to the nucleus. Finally, markers of osteogenic differentiation were determined by real-time PCR, western blotting, ALP assays and Alizarin Red S staining. Results ClC-3 chloride channels knockdown led to increased expression of Smad2/3 but no significant change in p38 or Erk1/2. Furthermore, ClC-3 chloride channels knockdown resulted in increases in the formation of the Smad2/3/4 complex and its translocation to the nucleus. In contrast, the inhibition of TGF-β1 receptors decreased the expression of Smad2, Smad3, p38, and Erk1/2 and the formation of the Smad2/3/4 complex. Finally, the expression of osteogenesis-related markers were decreased upon ClC-3 and Smad2/3/4 knockdown, but the degree to which these parameters were altered was decreased upon the knockdown of ClC-3 and Smad2/3/4 together compared to independent knockdown of ClC-3 or Smad2/3/4. Conclusions The Smad2/3 proteins respond to changes in ClC-3 chloride channels. The Smad2/3/4 signaling pathway inhibits osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells.

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ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

Cited by 5 publications

References 100 publications

Epigenetic and transcriptomic alterations in the ClC-3-deficient mice consuming a normal diet

Epigenetic and transcriptomic alterations in the ClC-3-deficient mice consuming a normal diet

Clcn3 deficiency ameliorates high-fat diet-induced obesity and improves metabolism in mice

The role of the Smad2/3/4 signaling pathway in osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells

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