Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice

Santos, Francisco; Correia, Bárbara; Marinho, Thatiany de Souza; Barbosa-da-Silva, Sandra; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

doi:10.1016/j.mce.2020.110804

Cited by 7 publications

(7 citation statements)

References 58 publications

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“…Additionally, we noted that the co-treatment with gemigliptin decreased the state of ER stress concurrently with activation of LX-2 cells. These results are consistent with previous studies on ER stress amelioration of DPP-4 inhibitors [23,[36][37][38].…”

Section: Discussionsupporting

confidence: 93%

“…Besides that, some DPP-4 inhibitors were reported to suppress ER stress in different organs of several models. In rodent livers, sitagliptin, saxagliptin and linagliptin were shown to attenuated markers of ER stress which was induced by methionine/choline-deficient diet, fructose and high fat diet, respectively [23,36,37]. Particularly, vildagliptin reduced ER dilation and UPR signaling in the liver of high fat diet mice [38].…”

Section: Discussionmentioning

confidence: 99%

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Gemigliptin alleviates succinate induced endoplasmic reticulum stress and activation of hepatic stellate cells

Nguyen

Park

et al. 2022

Preprint

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Background: Hepatic stellate cells (HSCs) activation is the principal event in the development of liver fibrosis in which succinate-GPR91 signaling has recently been shown to be a contributor. Moreover, endoplasmic reticulum (ER) stress has been reported to involve in HSC activation, but its association with succinate in pathogenesis of liver fibrosis remains scarce. In this study, we investigated the role of gemigliptin, an antidiabetic DDP-4 inhibitor, in the succinate-induced ER stress and activation of HSCs. Methods: LX-2 cells, the immortalized human HSCs, were treated with succinate and gemigliptin. For animal experiments, C57BL/6N mice were divided into 3 groups: control diet, high-fat high-cholesterol (HFHC) diet, and HFHC diet mixed with gemigliptin. Results: Succinate significantly induced HSC activation and increased expression of inflammatory markers and the increase in the migration of HSCs. The treatment of succinate also caused ER dilation and activated the unfolded protein response (UPR) signaling as PERK, eIF2alpha, Bip, suggesting increasing ER stress in HSCs. All responses of HSCs to succinate were attenuated with the co-treatment of gemigliptin. Moreover, the exposure of HSCs to tunicamycin, an inducer of ER stress, promoted the expression of α-SMA, proliferation and migration of HSCs. In vivo, the level of fibrotic and ER stress markers was increased in mice fed with HFHC diet and the administration of gemigliptin improved these changes in HFHC-induced mice. Conclusion: This study showed the involvement of ER stress in the activation of succinate-induced LX-2 HSCs and gemigliptin significantly reduced ER stress in HSC activation. Therefore, gemigliptin may become an anti-fibrotic agent and targeting to succinate and ER stress may be a promising therapeutic in the management of liver fibrosis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Gemigliptin alleviates succinate induced endoplasmic reticulum stress and activation of hepatic stellate cells

Nguyen

Park

et al. 2022

Preprint

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“…This is accompanied by increased mRNA expression of Atf4, Chop (C/EBP homologous protein), and Gadd45a in the liver, which is coupled with increased steatosis and inflammation. [136][137][138] The increased expression of these genes is aimed to induce apoptosis, to protect cells from excess ER stress. 137 A recent study has demonstrated that the PERK (protein kinase R-like ER kinase) branch of the unfolded protein response, which is activated during ER stress, boosts hepatocyte apoptosis via ATF4 by regulating Gadd45a expression, 136 while CHOP itself elicits Gadd45a gene expression to stimulate apoptosis (Figure 3).…”

Section: Regulatory Roles Of Gadd45a In Adipose Tissue and The Livermentioning

confidence: 99%

“…137 A recent study has demonstrated that the PERK (protein kinase R-like ER kinase) branch of the unfolded protein response, which is activated during ER stress, boosts hepatocyte apoptosis via ATF4 by regulating Gadd45a expression, 136 while CHOP itself elicits Gadd45a gene expression to stimulate apoptosis (Figure 3). 138 All these effects were prevented by the treatment with the PPARβ/ δ agonist GW0742 or the antidiabetic drugs linagliptin, a dipeptidyl peptidase-4 inhibitor, and empagliflozin, an inhibitor of the sodium glucose co-transporter-2. [137][138][139][140] In consonance with this, the GLP-1 receptor agonist semaglutide might be useful in controlling liver steatosis by reducing inflammation, insulin resistance, and ER stress through a mechanism involving GADD45A, and independently of weight loss or any effect on lipogenesis.…”

Section: Regulatory Roles Of Gadd45a In Adipose Tissue and The Livermentioning

confidence: 99%

“…138 All these effects were prevented by the treatment with the PPARβ/ δ agonist GW0742 or the antidiabetic drugs linagliptin, a dipeptidyl peptidase-4 inhibitor, and empagliflozin, an inhibitor of the sodium glucose co-transporter-2. [137][138][139][140] In consonance with this, the GLP-1 receptor agonist semaglutide might be useful in controlling liver steatosis by reducing inflammation, insulin resistance, and ER stress through a mechanism involving GADD45A, and independently of weight loss or any effect on lipogenesis. 136 In a rodent model of nonalcoholic steatohepatitis induced by methionine-and choline-deficient diet, Gadd45a suppression boosted hepatic inflammation, fibrosis, and apoptosis, which were accompanied by disrupted fatty acid metabolism and greater oxidative and ER stress.…”

Section: Regulatory Roles Of Gadd45a In Adipose Tissue and The Livermentioning

confidence: 99%

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GADD45A: With or without you

Palomer,

Salvador,

Griñán‐Ferré

et al. 2024

Medicinal Research Reviews

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The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non‐genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well‐known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP‐activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune‐related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.

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Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist

et al. 2021

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Anti-steatotic linagliptin pleiotropic effects encompasses suppression of de novo lipogenesis and ER stress in high-fat-fed mice

Cited by 7 publications

References 58 publications

Gemigliptin alleviates succinate induced endoplasmic reticulum stress and activation of hepatic stellate cells

Gemigliptin alleviates succinate induced endoplasmic reticulum stress and activation of hepatic stellate cells

GADD45A: With or without you

Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist

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