miR‐375 induces adipogenesis through targeting Erk1 in pancreatic duct cells under the influence of sodium palmitate

Gezginci‐Oktayoglu, Selda; Sancar, Serap; Karatug‐Kacar, Ayse; Bolkent, Şehnaz

doi:10.1002/jcp.30129

Cited by 11 publications

(6 citation statements)

References 61 publications

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“…Reports also indicate signs of dedifferentiation and loss of function in pancreatic islet β-cells in HFD mice [58] . Excessive saturated fatty acids may induce differentiation of pancreatic ductal cells into fat cells, leading to increased fat accumulation [59] . Currently, foundational reports on the pathogenic mechanism of NAFPD are lacking.…”

Section: Discussionmentioning

confidence: 99%

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signaling pathway

Yang,

Zhang,

et al. 2024

Preprint

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G protein-coupled receptor 119 (GPR119) agonists are being developed to safeguard the function of pancreatic β-cells, especially in the context of non-alcoholic fatty pancreas disease (NAFPD), closely associated with β-cell dysfunction arising from excessive fat accumulation in the pancreas. Drug repurposing technology, abandoning the drawbacks of traditional lengthy, costly, and low-market-probability development methods, has emerged as a new direction in drug development. Here, we employed a drug repurposing technology to screen GPR119 agonists and explore their potential molecular mechanisms for enhancing β-cell function in the context of NAFPD. Employing Schrodinger Suites drug design software, we found that 3622 drugs, including the α-1 adrenergic receptor blocker Terazosin, can bind to GPR119. Terazosin was was further validated to selectively activate GPR119, leading to increased cAMP and ATP synthesis, consequently enhancing insulin secretion. Terazosin administration improved high blood glucose, obesity, and impaired pancreatic β-cell function in NAFPD mice. It inhibited the upregulation of MST1-Foxo3a expression in pancreatic tissue and enhancing damaged mitophagy clearance, restoring autophagic flux, improving mitochondrial quantity and structure in β-cells. Notably, GPR119 deficiency negated the positive impact of Terazosin on pancreatic β-cell function in NAFPD mice, and abolished its inhibitory effect on the MST1-Foxo3a pathway. In conclusions, drug repurposing technology is applicable to the development of GPR119 agonists. Terazosin enhances mitophagy and alleviating β-cell dysfunction in the context of NAFPD by suppressing the MST1-Foxo3a signaling pathway. Terazosin could be considered a priority treatment for patients with concomitant NAFPD and hypertension.

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Section: Discussionmentioning

confidence: 99%

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signaling pathway

Yang,

Zhang,

et al. 2024

Preprint

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“…Gezginci-Oktayoglu et al . 50 reported that reducing miR-375 expression improved Erk1 expression in ARIP cells, and suppression of miR-375 suppressed the expression of the adipogenesis markers PPAR2, LPL, GLUT4, and leptin. Kraus et al .…”

Section: Discussionmentioning

confidence: 99%

SNPs in microRNA seed region and impact of miR-375 in concurrent regulation of multiple lipid accumulation-related genes

Lee,

Hong,

Lee

et al. 2024

Sci Rep

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Bovine intramuscular fat (IMF), commonly referred to as marbling, is regulated by lipid metabolism, which includes adipogenesis, lipogenesis, glycerolipid synthesis, and lipolysis. In recent years, breeding researchers have identified single nucleotide polymorphisms (SNPs) as useful marker-assisted selection tools for improving marbling scores in national breeding programs. These included causal SNPs that induce phenotypic variation. MicroRNAs (miRNAs) are small highly conserved non-coding RNA molecules that bind to multiple non-coding regions. They are involved in post-transcriptional regulation. Multiple miRNAs may regulate a given target. Previously, three SNPs in the GPAM 3ʹ UTR and four miRNAs were identified through in silico assays. The aim of this study is to verify the binding ability of the four miRNAs to the SNPs within the 3ʹUTR of GPAM, and to identify the regulatory function of miR-375 in the expression of genes related to lipid metabolism in mammalian adipocytes. It was verified that the four miRNAs bind to the GPAM 3ʹUTR, and identified that the miR-375 sequence is highly conserved. Furthermore, it was founded that miR-375 upregulated the GPAM gene, C/EBPα, PPARγ and lipid metabolism-related genes and promoted lipid droplet accumulation in 3T3-L1 cells. In conclusion, these results suggest that miR-375 is a multifunctional regulator of multiple lipid metabolism-related genes and may aid in obesity research as a biomarker.

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“…Long-term overexposure to saturated FA may cause the differentiation of ductal cells into adipocytes or βcells. 181 Additionally, lipotoxic stimulus (long-term high concentration of FAs) can evoke insulin production in ductal cells. Furthermore, rat pancreatic ductal cell line treatment with palmitate-induced fat accumulation and leptin release.…”

Section: Er Stress and Autophagymentioning

confidence: 99%

“…Furthermore, rat pancreatic ductal cell line treatment with palmitate-induced fat accumulation and leptin release. Gezginci-Oktayoglu et al 181 demonstrated that the suppression of Erk1 during saturated FA treatment can be the background mechanism for ductal cell adipogenesis. A high-fat diet induces TG and FFA elevation in the serum of experimental animals, 182,183 and it can affect pancreatic ductal function.…”

Section: Er Stress and Autophagymentioning

confidence: 99%

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Mechanisms linking hypertriglyceridemia to acute pancreatitis

et al. 2023

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Hypertriglyceridemia (HTG) is a metabolic disorder, defined when serum or plasma triglyceride concentration (seTG) is >1.7 mM. HTG can be categorized as mild to very severe groups based on the seTG value. The risk of acute pancreatitis (AP), a serious disease with high mortality and without specific therapy, increases with the degree of HTG. Furthermore, even mild or moderate HTG aggravates AP initiated by other important etiological factors, including alcohol or bile stone. This review briefly summarizes the pathophysiology of HTG, the epidemiology of HTG‐induced AP and the clinically observed effects of HTG on the outcomes of AP. Our main focus is to discuss the pathophysiological mechanisms linking HTG to AP. HTG is accompanied by an increased serum fatty acid (FA) concentration, and experimental results have demonstrated that these FAs have the most prominent role in causing the consequences of HTG during AP. FAs inhibit mitochondrial complexes in pancreatic acinar cells, induce pathological elevation of intracellular Ca2+ concentration, cytokine release and tissue injury, and reduce the function of pancreatic ducts. Furthermore, high FA concentrations can induce respiratory, kidney, and cardiovascular failure in AP. All these effects may contribute to the observed increased AP severity and frequent organ failure in patients. Importantly, experimental results suggest that the reduction of FA production by lipase inhibitors can open up new therapeutic options of AP. Overall, investigating the pathophysiology of HTG‐induced AP or AP in the presence of HTG and determining possible treatments are needed.

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miR‐375 induces adipogenesis through targeting Erk1 in pancreatic duct cells under the influence of sodium palmitate

Cited by 11 publications

References 61 publications

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signaling pathway

Terazosin, a repurposed GPR119 agonist, ameliorates mitophagy and β-cell function in NAFPD by inhibiting MST1-Foxo3a signaling pathway

SNPs in microRNA seed region and impact of miR-375 in concurrent regulation of multiple lipid accumulation-related genes

Mechanisms linking hypertriglyceridemia to acute pancreatitis

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