KLF10 transcription factor regulates hepatic glucose metabolism in mice

Yang, Xiaoying; Chen, Qi; Sun, Lihong; Zhang, Huabing; Lü, Yan; Cui, Xiaona; Gao, Yong; Fang, Fude; Chang, Yongsheng

doi:10.1007/s00125-017-4412-2

Cited by 33 publications

(27 citation statements)

References 33 publications

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“…Notably, KLF10 is the most up‐regulated gene in the 86 selected genes and its association with kidney disease is not yet known. KLF10 was originally identified as a TGF‐β‐inducible early gene 1 (TIEG) in human osteoblasts and often functions as a transcriptional repressor involved in multiple cellular processes (Subramaniam et al , , ; McConnell & Yang, ; Yang et al , ). We therefore decided to further investigate the role of KLF10 in podocyte injury.…”

Section: Resultsmentioning

confidence: 99%

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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Diabetic nephropathy is the leading cause of end‐stage renal disease. Although dysfunction of podocytes, also termed glomerular visceral epithelial cells, is critically associated with diabetic nephropathy, the mechanism underlying podocyte dysfunction still remains obscure. Here, we identify that KDM 6A, a histone lysine demethylase, reinforces diabetic podocyte dysfunction by creating a positive feedback loop through up‐regulation of its downstream target KLF 10. Overexpression of KLF 10 in podocytes not only represses multiple podocyte‐specific markers including nephrin, but also conversely increases KDM 6A expression. We further show that KLF 10 inhibits nephrin expression by directly binding to the gene promoter together with the recruitment of methyltransferase Dnmt1. Importantly, inactivation or knockout of either KDM 6A or KLF 10 in mice significantly suppresses diabetes‐induced proteinuria and kidney injury. Consistent with the notion, we also show that levels of both KDM 6A and KLF 10 proteins or mRNA s are substantially elevated in kidney tissues or in urinary exosomes of human diabetic nephropathy patients as compared with control subjects. Our findings therefore suggest that targeting the KDM 6A– KLF 10 feedback loop may be beneficial to attenuate diabetes‐induced kidney injury.

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Section: Resultsmentioning

confidence: 99%

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

et al. 2019

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“…KLF10 could be added to the growing list of KLF family members which function in the regulation of adipogenesis. The role of KLF10 in metabolism had been defined in the liver (39,40). But it is still unknown whether KLF10 also plays a role in the metabolism of other tissues.…”

Section: Resultsmentioning

confidence: 99%

Krüppel-like factor 10 (KLF10) is transactivated by the transcription factor C/EBPβ and involved in early 3T3-L1 preadipocyte differentiation

Liu

Peng

Guo

et al. 2018

Journal of Biological Chemistry

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“…In C57BL/6 mice, the mRNA and protein expression level of KLF10 was significantly increased in diet-induced non-alcoholic steatohepatitis and collagen producing activated hepatic stellate cells (21). Klf10 expression was upregulated in the livers of diabetic and obese ob/ob mice and that knockdown of Klf10 significantly inhibited the hepatic expression of gluconeogenic genes, decreased blood glucose levels and improved glucose tolerance (19). Our study showed that EMP treatment could obviously reduce the expression level of Klf10 (Figures 4C, 6D).…”

Section: Discussionmentioning

confidence: 98%

“…GO analysis revealed that EMP treatment significantly downregulated genes in the metal ion binding pathway ( Figure 4B), which involved in various biological functions, include lipid and glucose metabolism (such as Klf10, Atp2a2, and Enpp2), mitochondrial function (such as Ndufs1, Oma1, and Pde12) and β-cell function (such as Atp2a2 and Vav2), et al Our study showed that EMP treatment could significantly improve glucose tolerance and dyslipidemia, and alleviate insulin resistance in T2D rats ( Table 2 and Figure 1C), which may be associated with the effect of EMP on the expression of related genes in the metal ion binding pathway. KLF10 is a member of the Krüppel-like family of transcription factors (Klfs), which has been shown to be implicated in many biological processes, including cell differentiation, apoptosis and glucose metabolism (17)(18)(19)(20). In C57BL/6 mice, the mRNA and protein expression level of KLF10 was significantly increased in diet-induced non-alcoholic steatohepatitis and collagen producing activated hepatic stellate cells (21).…”

Section: Discussionmentioning

confidence: 99%

Liver Transcriptomic Reveals Novel Pathways of Empagliflozin Associated With Type 2 Diabetic Rats

Xiang

et al. 2020

Front. Endocrinol.

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The hypoglycaemic target of empagliflozin (EMP), as a novel inhibitor of sodium-glucose cotransporter (SGLT2), is clear. However, recent studies have shown that EMP also has an important role in lipid metabolism and cardiovascular diseases. The liver plays an important role in the development of type 2 diabetes (T2D), although whether EMP affects liver glucose metabolism is currently not reported. This study was designed to evaluate the effect of EMP on hepatic glucose metabolism in T2D and the underlying mechanism. A model of T2D was established by a high-fat and glucose diet (HFD) combined with streptozotocin (30 mg/kg) in male Wistar rats. Serum samples were collected to measure biochemical indicators, and liver samples were extracted for RNA-seq assay. Quantitative real-time PCR (qPCR) was used to further verify the gene expression levels detected by the RNA-seq assay. The EMP group showed significantly decreased blood glucose, triglyceride, cholesterol, non-esterified fatty acid and low-density lipoprotein cholesterol levels, and increased high-density lipoprotein cholesterol levels in serum compared with the type 2 diabetes model (MOD) group. Furthermore, EMP decreased the levels of inflammatory factors IL-1β, IL-6, and IL-8 in the serum compared to the MOD. Liver transcriptome analysis showed EMP affects a large number of upregulated and downregulated genes. Some of these genes are novel and involve in the metal ion binding pathway and the negative regulation of transcription from the RNA polymerase II promoter pathway, which are also closely related to glucolipid metabolism and insulin signaling. Our study provides new knowledge about the mechanism through which SGLT inhibitor can offer beneficial effects in T2D and especially in the hepatic metabolism. These genes found in this study also laid a solid foundation for further research on the new roles and mechanisms of EMP.

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KLF10 transcription factor regulates hepatic glucose metabolism in mice

Abstract: KLF10 is an important regulator of hepatic glucose metabolism and modulation of KLF10 expression in the liver may be an attractive approach for the treatment of type 2 diabetes.

Cited by 33 publications

References 33 publications

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

A KDM6A–KLF10 reinforcing feedback mechanism aggravates diabetic podocyte dysfunction

Krüppel-like factor 10 (KLF10) is transactivated by the transcription factor C/EBPβ and involved in early 3T3-L1 preadipocyte differentiation

Liver Transcriptomic Reveals Novel Pathways of Empagliflozin Associated With Type 2 Diabetic Rats

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