Interaction of Nuclear Receptor Subfamily 4 Group A Member 1 (Nr4a1) and Liver Linase B1 (LKB1) Mitigates Type 2 Diabetes Mellitus by Activating Monophosphate-Activated Protein Kinase (AMPK)/Sirtuin 1 (SIRT1) Axis and Inhibiting Nuclear Factor-kappa B (NF-κB) Activation

Abstract

Departmental sources Background: Nuclear receptor subfamily 4 group A member 1 (Nr4a1) has been increasingly investigated in association with type 2 diabetes mellitus (T2DM). This study aimed to explore its efficacy with liver kinase B1 (LKB1) and potential signaling pathways in T2DM. Material/Methods: A T2DM model in rats was established by high-fat diet and injection of 30 mg/kg streptozotocin. The ectopic expression of Nr4a1 or in combination with LKB1 was performed in T2DM rats to probe their effects on T2DM. Then, the weight and indicators of blood lipid and blood glucose in normal rats and T2DM rats were measured. The volume change of adipocytes and the size of lipid droplets in white adipose tissue (WAT) were observed by hematoxylin-eosin staining and oil red O staining, respectively. We also measured levels of Nr4a1, LKB1, and adenosine monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/Nuclear factor-kappa B (NF-kB) axis-related proteins. Result: In T2DM rats, Nr4a1 was highly expressed, and body weight, blood lipid and blood glucose were increased, and the volume of adipocytes and the size of lipid droplets in WAT were increased, which were all reversed by low expression of Nr4a1. After treatment with Nr4a1 and LKB1 together, T2DM rats showed decreased levels of blood lipid, blood glucose, and reduced volume of adipocytes and lipid droplet size in WAT, with activated AMPK/SIRT1 signaling pathway and inhibited NF-kB. Conclusions: Our results highlight that interaction of Nr4a1 and LKB1 can mitigate T2DM by activating the AMPK/SIRT1 signaling pathway and inhibiting NF-kB activation. This may offer new insight for T2DM treatment.

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

“…Neutrophil degranulation [52], innate immune system [53], platelet degranulation [54], extracellular matrix organization [55], diseases of glycosylation [56], platelet activation, signaling and aggregation [57], hemostasis [58], secretion [59], secretory vesicle [60], transmembrane transporter activity [61], cell adhesion [62], localization of cell [63], extracellular matrix [55], intrinsic component of plasma membrane [64], structural molecule activity [65], signaling receptor binding [66], have been highly noted in T2DM. Reports indicate that HIF1A [67], HLA-DRB1 [68], CHI3L1 [69], ADORA2A [70], ADRB2 [71], CLU (clusterin) [72], AGT (angiotensinogen) [73], VCAM1 [74], PPARA (peroxisome proliferator activated receptor alpha) [75], APOL1 [76], ZFP36 [77], PPM1B [78], SOCS1 [79], SNCA (synuclein alpha) [80], CTSS (cathepsin S) [81], IL6R [82], CFB (complement factor B) [83], DEFB1 [84], VNN1 [85], RAB27A [86], DPP4 [87], RARRES2 [88], CASP1 [89], LCN2 [90], REG3A [91], CD74 [92], PCSK2 [93], CHGB (chromogranin B) [94], TTR (transthyretin) [95], LRG1 [96], ALB (albumin) [97], DPP7 [98], APOH (apolipoprotein H) [99], CTSD (cathepsin D) [100], GCG (glucagon) [101], KCNQ1 [102], NR4A1 [103], PLIN5 [104], ALDH2 [105], ANG (angiogenin) [106], CLDN7 [107], PRLR (prolactin receptor) [108], SOD2 [109], MLXIPL (MLX interacting protein like) [110], CTSD (cathepsin D) [111], PECAM1 [112], ADA (adenosine deaminase) [113], MFGE8 [114], COL1A1 [115], COL3A1 [116], NID2 [117], ARG1 [118], CD93 [119], IGF2 […”

“…Emmens et al [39] found that PENK (proenkephalin) expression was up regulated in cardiovascular diseases, but this gene might be responsible for progression of T2DM. Recent studies have proposed that the SAA1 [ [101], KCNQ1 [102], NR4A1 [103], PLIN5 [104], ALDH2 [105], ANG (angiogenin) [106], CLDN7 [107], PRLR (prolactin receptor) [108], SOD2 [109], MLXIPL (MLX interacting protein like) [110], CTSD (cathepsin D) [111], PECAM1 [112], ADA (adenosine deaminase) [113], MFGE8 [114], COL1A1 [115], COL3A1 [116], NID2 [117], ARG1 [118], CD93 [119], IGF2 [120], IL18 [121], LAMA1 [122], HPSE (heparanase) [123], BMP4 [124], CXCR4 [125], KDR (kinase insert domain receptor) [126], ESAM (endothelial cell adhesion molecule) [127], THBS1 [128], CD34 [129], SERPINE1 [130], WNT5B [131], MGP (matrix Gla protein) [132], MMP3 [133], MMP9 [134], MMP11 [135], IL16 [136], TNFRSF11B [137], TIMP3 [138] and CAPN3 [139] were found in T2DM. HLA-A [140], HLA-B [141], HLA-C [142], HLA-DPB1 [143], HLA-E [144], ERBB3 [145], MFAP4 [146] and JAK3…”

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases

“…As a secondary and long-term effect, AMPK phosphorylates TFs SREBP1c and ChREBP, thus inhibiting the transcription of subsequent lipogenic genes [65]. Sirtuin proteins (SIRT1 and SIRT3) stimulate AMPK via deacetylation of its upstream activator LKB1 (liver kinase B1) [66]. Nowadays, sirtuins are recognised as crucial regulators of lipid metabolism, providing tissue-specific FAO-promoting activities (in skeletal muscle and liver), lipolysis (in adipose tissue), mitochondrial respiration (BAT (brown adipose tissue)), and food intake (in the hypothalamus) [67].…”

Etnobotánica, etnofarmacología y toxicidad de Geranium ayavacense Willd. ex Kunth y Geranium sessiliflorum Cav. (Geraniaceae): Una revisión

“…Otro probable mecanismo, es a través de la sirtuina-1 (SIRT1), proteína implicada en procesos de antienvejecimiento y antiinflamatorio, evidenciando una restricción calórica durante su activación (Penumetcha & Santanam 2012). La SIRT-1 dependiente de la deacetilación del PPARg ha demostrado una forma de modulación selectiva en este receptor, permitiendo la inducción de los genes BAT (tejido adiposo marrón) y supresión de los genes WAT (tejido adiposo blanco) viscerales, asociados con la resistencia a insulina (Qiang et al 2012;Ming et al 2020). Asimismo, flavonoides como quercetina, tienen efecto hipoglucemiante sobre la alfa-glucosidasa favoreciendo la fosforilación de la glucosa, para formar glucosa 6-fosfato, paso limitante para la glucólisis y regulación de la glicemia (Karato et al 2006 2015), prueba de ello es que se evidencia reportes discordantes de su actividad antibacteriana, incluso tratándose de la misma especie vegetal (Tabla 4).…”