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Glucocorticoid Signaling in the Heart
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Cardiac-specific knockout (KO) of GR generated by mating αMHC-Cre to Floxed GR mice showed no obvious difference compared to wild-type (Wt) littermates at birth or early in life. However, these mice developed spontaneous progressive pathological cardiac hypertrophy by 3 months with associated left-ventricular dysfunction, but no interstitial fibrosis. Loss of GR function results in increased mortality by 5 months of age due to heart failure. Microarray analysis on hearts from 1-month- and 2-month-old mice show increases in the expression of genes involved in inflammation and immune response, which are further dysregulated by 3 months of age contributing to cardiac dysfunction. In addition, a decrease in cardiac-enriched and functional genes like calcium handling gene RyR2 and transcriptional regulator Klf15 is observed. Ingenuity pathway analysis characterized these dysregulated genes as those involved in “cardiovascular diseases” (45). A similar hypertrophic phenotype is observed after 6 months in mice subjected to adrenalectomy at 1 month of age. Transcriptome analysis in these hearts reveals the dysregulation of genes involved in cardiac hyper-trophy and arrythmias. Interestingly, supplementation with exogenous corticosterone reverses left-ventricular dysfunction and hypertrophic phenotype; however, the EKG changes of prolonged QT and QTc observed in adrenalectomized mice persist, which are reversible with aldosterone treatment (46). Characterization of cardiac-specific double knockout of GR and MR (cGRMRdKO) in comparison with GR (cGRKO) and MR (cMRKO) knockouts alone reveals the critical role of GR in cardiac physiology. On the other hand, activated MR signaling is seen as detrimental for cardiac function. Although the cGRMRdKO mice displayed altered gene regulation, as seen in cGRKO, these mice did not develop spontaneous cardiac pathology. Similarly, no obvious cardiac phenotype is observed in cMRKO mice. Genome-wide microarray analysis of transcriptome in these KO models shows the differential regulation of genes that could be contributing to the cardiac pathogenesis in cGRKO mice and include genes involved in Ca2+ handling, oxidative stress, and cell death. In addition, cGRMRdKO mice also showed an increase in cardioprotective genes like Ccnd2, Hdac4, and Ankrd23, accompanied by a decrease in Agt (47). These genes have been shown to be involved in regulating cardiac hypertrophy and survival and, thus, were restricting cardiac enlargement and dysfunction in cGRMRdKO compared to cGRKO (47). Work overload, in the form of excessive exercise or transverse aortic constriction (TAC) induced pressure overload, results in a decrease in GR expression and dependent gene transcription. This decrease is associated with the development of pathological cardiac hypertrophy and dysfunction (48) (49).
Diacylglycerol kinase epsilon protects against renal ischemia/reperfusion injury in mice through Krüppel-like factor 15/klotho pathway
Published in Renal Failure, 2022
Ziying Wang, Zhuanli Zhou, Yanan Zhang, Fuwen Zuo, Junyao Du, Mingwei Wang, Muchen Hu, Yu Sun, Xiaojie Wang, Min Liu, Yan Zhang, Wei Tang, Fan Yi
Moreover, we also found that DGKE regulated the expression of Klotho, which was initially identified as an antiaging protein and is also mainly expressed in the kidney [29]. Numerous studies have indicated that Klotho is significantly correlated with the development and progression of AKI and CKD. Exogenous supplementation or overexpression of endogenous Klotho prevents and ameliorates injury, promotes recovery, and suppresses fibrosis to mitigate the development of CKD [30,31]. Therefore, Klotho is considered as a potential diagnostic biomarker and therapeutic target for the prevention of kidney injury [32]. However, the endogenous regulation of Klotho expression, release, and metabolism remains largely unknown. Considering that KLF15 is an important transcription factor involved in AKI, and that both Klotho and KLF15 are regulated by DGKE in this study, we therefore examined the interaction between Klotho and KLF15. Our results showed that Klf15 gene silencing counteracted the effects of DGKE on Klotho expression. However, pretreatment with exogenous recombinant Klotho protein had no effects on KLF15 and DGKE expression, indicating that Klotho might be a downstream target of KLF15 directly or indirectly. Therefore, although our current data are very limited, we proposed that DGKE-induced Klotho expression is mediated, at least in part, by KLF15. Further studies are needed to detect whether Klotho expression is directly regulated by KLF15.
Metformin: evidence from preclinical and clinical studies for potential novel applications in cardiovascular disease
Published in Expert Opinion on Investigational Drugs, 2023
Adel Dihoum, Graham Rena, Ewan R Pearson, Chim C Lang, Ify R Mordi
There is also evidence that metformin inhibits hepatic glucose production via its inhibitory effect on the Kruppel-like factor 15 (KLF15) protein and gene expression, an important regulator of gluconeogenesis. In hepatocytes, KLF-15 plays a critical role in the regulation of gene expression for gluconeogenesis and amino acid-degrading enzymes [19]. Metformin, however, induces the proteasomal degradation of KLF15 by promoting its ubiquitination [19]. This has raised the possibility that the inhibitory effect of metformin on gluconeogenesis is mediated at least in part, by downregulation of KLF-15 and subsequent attenuation of expression of such genes [19].
Reduced branched-chain aminotransferase activity alleviates metabolic vulnerability caused by dim light exposure at night in Drosophila
Published in Journal of Neurogenetics, 2023
Mari Kim, Gwang-Ic Son, Yun-Ho Cho, Gye-Hyeong Kim, Sung-Eun Yoon, Young-Joon Kim, Jongkyeong Chung, Eunil Lee, Joong-Jean Park
Several possibilities are considered for explaining how the circadian system regulates BCAA metabolism. First, the expression of Bcat can be controlled by binding of circadian factors to the E-box present around Bcat. We investigated E-box distribution, a target site of the BMAL1/CLOCK complex, inside and outside Bcat, bckdhA, and bckdhB genes (Supplementary Table 1). While more than 15 E-boxes were present around per and tim genes, 8 were found in Bcat, none in bckdhA, and 3 in bckdhB. If BCAA metabolism is under the direct control of the circadian regulatory system, Bcat should be the primary target. However, verifying whether the CLOCK/CYCLE complex binds to these E-boxes and regulates Bcat expression is necessary. Second, the circadian system can regulate BCAA metabolism through Krüppel-like factor 15 (KLF15). KLF15 is a C2H2-type zinc finger transcription factor and regulates the expression of enzymes involved in nitrogen homeostasis in a clock-dependent manner (Jeyaraj et al., 2012). KLF15 controls the circadian rhythm of BCAA metabolism in the mouse liver and muscle (Fan et al., 2018; Jeyaraj et al., 2012). In the fasting state, KLF15 upregulates BCAT2 to inhibit lipogenesis and promote gluconeogenesis in the liver (Gray et al., 2007). Also, when the circadian rhythm is disrupted, KLF15 expression increases. The expression levels of KLF15 mRNA and protein increased in per3 null mutant mice and decreased in a per3 overexpression model (Aggarwal et al., 2017). It should be interesting to determine whether metabolic sensitization appears after exposure to LAN in Klf15 (CG2932) mutant flies. Third, the circadian system can regulate BCAA metabolism through microRNAs. MiR-277, activated by dCLOCK/CYCLE, interacts with PAR-domain protein 1 (Pdp1) mRNA (Xia et al., 2019). Overexpression of Drosophila miR-277 inhibits BCAT activity and induces mTOR activity and BCAA accumulation (Esslinger et al., 2013). Therefore, it is necessary to confirm the role of microRNAs in regulating BCAA metabolism.