MiR-146a-5p targeting SMAD4 and TRAF6 inhibits adipogenensis through TGF-β and AKT/mTORC1 signal pathways in porcine intramuscular preadipocytes

Zhang, Que; Cai, Rui; Tang, Guorong; Zhang, Wanrong; Pang, Wei

doi:10.1186/s40104-020-00525-3

Cited by 41 publications

(21 citation statements)

References 49 publications

(52 reference statements)

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“…miR-92a protected pancreatic β cells function by targeting KLF2 in diabetes (Wang et al, 2018). miR-146a inhibited adipogenensis through TGF-β and AKT/mTORC1 signal pathways by targeting SMAD4 and TRAF6 in porcine intramuscular preadipocytes (Zhang et al, 2021). miR-125b-5p could suppresses atherosclerotic plaque formation via inhibiting Map4k4 (Lin et al, 2021).…”

Section: Milk-derived Evs and Metabolic Regulationmentioning

confidence: 99%

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Jiang

You

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are released by all cells under pathological and physiological conditions. EVs harbor various biomolecules, including protein, lipid, non-coding RNA, messenger RNA, and DNA. In 2007, mRNA and microRNA (miRNA) carried by EVs were found to have regulatory functions in recipient cells. The biological function of EVs has since then increasingly drawn interest. Breast milk, as the most important nutritional source for infants, contains EVs in large quantities. An increasing number of studies have provided the basis for the hypothesis associated with information transmission between mothers and infants via breast milk-derived EVs. Most studies on milk-derived EVs currently focus on miRNAs. Milk-derived EVs contain diverse miRNAs, which remain stable both in vivo and in vitro; as such, they can be absorbed across different species. Further studies have confirmed that miRNAs derived from milk-derived EVs can resist the acidic environment and enzymatic hydrolysis of the digestive tract; moreover, they can be absorbed by intestinal cells in infants to perform physiological functions. miRNAs derived from milk EVs have been reported in the maturation of immune cells, regulation of immune response, formation of neuronal synapses, and development of metabolic diseases such as obesity and diabetes. This article reviews current status and advances in milk-derived EVs, including their history, biogenesis, molecular contents, and biological functions. The effects of milk-derived EVs on growth and development in both infants and adults were emphasized. Finally, the potential application and future challenges of milk-derived EVs were discussed, providing comprehensive understanding and new insight into milk-derived EVs.

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Section: Milk-derived Evs and Metabolic Regulationmentioning

confidence: 99%

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Jiang

You

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…In contrast to these findings, Zhang et al [ 45 ] found that miR-146a-5p expression first increased and then decreased during porcine intermuscular preadipocyte differentiation. A possible reason for this difference is that in-vivo preadipocyte differentiation is affected by adjacent tissues and multiple hormones.…”

Section: Discussionmentioning

confidence: 88%

“…Recent research has shown that some miRNAs participate in adipocyte differentiation; miR-16-5p and Bat-miR-204 promote it, and miR-125a-5p and miR-23a inhibit it [ 13 – 16 ]. MiR-146a-5p was found to inhibit the differentiation of intramuscular preadipocytes via Akt/mTORC1 signaling in a porcine model [ 17 ], whereas Francisco et al [ 18 ] observed elevated miR-146a-5p expression in differentiated human adipocytes. This miRNA is known to participate in the pathological processes of multiple metabolism-related diseases and obesity [ 19 – 24 ], but its role in adipocyte differentiation remains unclear.…”

Section: Introductionmentioning

confidence: 99%

MiR-146a-5p, targeting ErbB4, promotes 3T3-L1 preadipocyte differentiation through the ERK1/2/PPAR-γ signaling pathway

et al. 2022

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Background MicroRNAs (MiRNAs) are known to participate in preadipocyte differentiation, but the manner in which miR-146a-5p participates in this process remains unclear. This study was performed to examine the participation of miR-146a-5p in 3T3-L1 cell differentiation. Material and Methods miR-146a-5p expression was upregulated and down-regulated to examine effects on 3T3-L1 cell differentiation. Bioinformatics analysis was performed to predict its target genes, and the signaling pathway it regulates was identified by qRT-PCR and Western blotting. The expression of miR-146a-5p in epididymal adipose tissue from obese mice and in an obese mouse adipose cell model was examined by qRT-PCR. Results 3T3-L1 cells differentiated into mature adipocytes successfully, as verified by increased areas of intracellular lipid droplets and elevated expression of mature adipocyte markers, and these cells had elevated miR-146a-5p expression. The intracellular lipid droplet and triglyceride contents and the expression of mature adipocyte markers were significantly increased in miR-146a-5p–overexpressing 3T3-L1 cells and markedly decreased in miR-146a-5p–inhibited 3T3-L1 cells. ErbB4 was a predicted target gene of miR-146a-5p. In miR-146a-5p–overexpressing 3T3-L1 cells, ErbB4 expression and ERK1/2 phosphorylation were decreased and the expression of PPAR-γ was increased; the opposite was observed in miR-146a-5p–inhibited 3T3-L1 cells. In addition, miR-146a-5p expression was significantly increased in the mouse epididymal adipose tissue and adipose cell model. Conclusions Upregulated miR-146a-5p expression was related to 3T3-L1 cell differentiation. MiR-146a-5p promoted 3T3-L1 cell differentiation by targeting ErbB4 and via the ERK1/2/PPAR-γ signaling pathway.

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“…Activated Smad2 and Smad3 dimerize and together with Smad4 bind to SBEs in the Iα promoter, thereby initiating germline Iα-Cα transcription, the first step in CSR to IgA ( 62 ). Prompted by luciferase reporter assays showing miR-146a targeting of SMAD4 mRNA 3’UTR ( 63 – 65 ), we used miRNA-mRNA complementarity prediction tools (TargetScan.org, miRNA.org and miRbase.org) to identify miR-146a-specific target sites in the 3’UTRs of human and mouse Smad2/SMAD2, Smad3/SMAD3 and Smad4/SMAD4 ( Figure 6A ), suggesting a potentially silencing of Smad2, Smad3 and Smad4 by miR-146a in both human and mouse B cells. This implies that the miR-146a expression level, which is high in resting B cells, must be dampened by those stimuli that induce CSR to IgA to free Smad2/SMAD2, Smad3/SMAD3 and Smad4/SMAD4 genes from miR-146a silencing for CSR to IgA to unfold.…”

Section: Resultsmentioning

confidence: 99%

Epigenetic Modulation of Class-Switch DNA Recombination to IgA by miR-146a Through Downregulation of Smad2, Smad3 and Smad4

Casali

Morales

et al. 2021

Front. Immunol.

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IgA is the predominant antibody isotype at intestinal mucosae, where it plays a critical role in homeostasis and provides a first line of immune protection. Dysregulation of IgA production, however, can contribute to immunopathology, particularly in kidneys in which IgA deposition can cause nephropathy. Class-switch DNA recombination (CSR) to IgA is directed by TGF-β signaling, which activates Smad2 and Smad3. Activated Smad2/Smad3 dimers are recruited together with Smad4 to the IgH α locus Iα promoter to activate germline Iα-Cα transcription, the first step in the unfolding of CSR to IgA. Epigenetic factors, such as non-coding RNAs, particularly microRNAs, have been shown to regulate T cells, dendritic cells and other immune elements, as well as modulate the antibody response, including CSR, in a B cell-intrinsic fashion. Here we showed that the most abundant miRNA in resting B cells, miR-146a targets Smad2, Smad3 and Smad4 mRNA 3’UTRs and keeps CSR to IgA in check in resting B cells. Indeed, enforced miR-146a expression in B cells aborted induction of IgA CSR by decreasing Smad levels. By contrast, upon induction of CSR to IgA, as directed by TGF-β, B cells downregulated miR-146a, thereby reversing the silencing of Smad2, Smad3 and Smad4, which, once expressed, led to recruitment of Smad2, Smad3 and Smad4 to the Iα promoter for activation of germline Iα-Cα transcription. Deletion of miR-146a in miR-146a–/– mice significantly increased circulating levels of steady state total IgA, but not IgM, IgG or IgE, and heightened the specific IgA antibody response to OVA. In miR-146a–/– mice, the elevated systemic IgA levels were associated with increased IgA+ B cells in intestinal mucosae, increased amounts of fecal free and bacteria-bound IgA as well as kidney IgA deposition, a hallmark of IgA nephropathy. Increased germline Iα-Cα transcription and CSR to IgA in miR-146a–/– B cells in vitro proved that miR-146a-induced Smad2, Smad3 and Smad4 repression is B cell intrinsic. The B cell-intrinsic role of miR-146a in the modulation of CSR to IgA was formally confirmed in vivo by construction and OVA immunization of mixed bone marrow μMT/miR-146a–/– chimeric mice. Thus, by inhibiting Smad2, Smad3 and Smad4 expression, miR-146a plays an important and B cell intrinsic role in modulation of CSR to IgA and the IgA antibody response.

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MiR-146a-5p targeting SMAD4 and TRAF6 inhibits adipogenensis through TGF-β and AKT/mTORC1 signal pathways in porcine intramuscular preadipocytes

Cited by 41 publications

References 49 publications

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

Biological Properties of Milk-Derived Extracellular Vesicles and Their Physiological Functions in Infant

MiR-146a-5p, targeting ErbB4, promotes 3T3-L1 preadipocyte differentiation through the ERK1/2/PPAR-γ signaling pathway

Epigenetic Modulation of Class-Switch DNA Recombination to IgA by miR-146a Through Downregulation of Smad2, Smad3 and Smad4

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