Hepatocyte Rap1a contributes to obesity- and statin-associated hyperglycemia

Wang, Yating; Spolitu, Stefano; Zadroga, John A.; Sarecha, Amesh K.

doi:10.1016/j.celrep.2022.111259

Cited by 10 publications

(29 citation statements)

References 79 publications

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“…Of note, the response to mechanical cues has specificity for the type of tissue and for cell type, due to the spatial location of the tissue and the threshold that the cell can withstand [ 44 ]. As a GTPase, Rap1 is normally in the active GTP-bound form; it is the main regulator of actin dynamics and is very important in the formation of cell movement connections [ 45 , 46 ]. Moreover, Rap1 is also a sensor of ECM stiffness [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Zhang

Wang

et al. 2023

Cell Commun Signal

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The integrity of the structure and function of the endometrium is essential for the maintenance of fertility. However, the repair mechanisms of uterine injury remain largely unknown. Here, we showed that the disturbance of mechanical cue homeostasis occurs after uterine injury. Applying a multimodal approach, we identified YAP as a sensor of biophysical forces that drives endometrial regeneration. Through protein activation level analysis of the combinatorial space of mechanical force strength and of the presence of particular kinase inhibitors and gene silencing reagents, we demonstrated that mechanical cues related to extracellular matrix rigidity can turn off the Rap1a switch, leading to the inactivation of ARHGAP35and then induced activation of RhoA, which in turn depends on the polymerization of the agonist protein F-actin to activate YAP. Further study confirmed that mechanotransduction significantly accelerates remodeling of the uterus by promoting the proliferation of endometrial stromal cells in vitro and in vivo. These studies provide new insights into the dynamic regulatory mechanisms behind uterine remodeling and the function of mechanotransduction.

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Section: Discussionmentioning

confidence: 99%

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Zhang

Wang

et al. 2023

Cell Commun Signal

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“…Experiments were conducted in 8–12-week-old, male, C57BL/6 mice unless otherwise specified. Animal numbers for the experiments were pre-calculated based on the reported similar studies from us and other laboratories with 80% power [ 28 , 32 , 47 ]. The basic characteristics of our model animals were reported, and all physiological and biochemical measurements were performed in double-blinded fashion.…”

Section: Methodsmentioning

confidence: 99%

Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity

Qiao

Ma²,

Jin³

et al. 2022

IJMS

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Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear. Here we show that in response to glucagon, Sam68 increases CREB/CRTC2 transactivity by interacting with CRTC2 in the CREB/CRTC2 complex and occupying the CRE motif of promoters, leading to gluconeogenic gene expression and glucose production. In hepatocytes, glucagon promotes Sam68 nuclear import, whereas insulin elicits its nuclear export. Furthermore, ablation of Sam68 in hepatocytes protects mice from high-fat diet (HFD)-induced hyperglycemia and significantly increased hepatic and peripheral insulin sensitivities. Thus, hepatic Sam68 potentiates CREB/CRTC2-mediated glucose production, contributes to the pathogenesis of insulin resistance, and may serve as a therapeutic target for T2D.

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“…36 Because Rap1a activity is decreased upon statins and adding back geranylgeranyl isoprenoids restores hepatic Rap1a activity, we became interested in the role of GGPP and Rap1a in statin-mediated PCSK9 induction. 36 In this study, we show that restoration of GGPP levels in statin treated mice lowers statin-induced PCSK9 and further decreases plasma LDL-C, independent of a change in Pcsk9 mRNA.…”

Section: Statinsmentioning

confidence: 99%

“…35 In addition to its LDL-C lowering effect, we recently showed that activation of Rap1a suppresses hepatic glucose production and its inhibition contributes to obesity-induced glucose intolerance. 36 Further, statins decrease Rap1a prenylation and activity in isolated hepatocytes and human liver samples and this may in turn explain their hyperglycemic effects. 36…”

Section: Introductionmentioning

confidence: 99%

Geranylgeranyl Isoprenoids and Hepatic Rap1a Regulate Basal and Statin-Induced Expression of PCSK9

Wang,

Tinsley,

Spolitu

et al. 2023

Preprint

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Low-density lipoprotein cholesterol (LDL-C) lowering is the main goal of atherosclerotic cardiovascular disease prevention, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is now a validated therapeutic strategy that lowers serum LDL-C and reduces coronary events. Ironically, the most widely used medicine to lower cholesterol, statins, has been shown to increase circulating PCSK9 levels, which limits their efficacy. Here, we show that geranylgeranyl isoprenoids and hepatic Rap1a regulate both basal and statin induced expression of PCSK9 and contribute to LDL-C homeostasis. Rap1a prenylation and activity is inhibited upon statin treatment, and statin mediated PCSK9 induction is dependent on geranylgeranyl synthesis and hepatic Rap1a. Accordingly, treatment of mice with a small molecule activator of Rap1a lowered PCSK9 protein and plasma cholesterol and inhibited statin mediated PCSK9 induction in hepatocytes. The mechanism involves inhibition of the downstream RhoA-ROCK pathway and regulation of PCSK9 at the post transcriptional level. These data further identify Rap1a as a novel regulator of PCSK9 protein and show that blocking Rap1a prenylation through lowering geranylgeranyl levels contributes to statin-mediated induction of PCSK9.

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Hepatocyte Rap1a contributes to obesity- and statin-associated hyperglycemia

Cited by 10 publications

References 79 publications

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Extracellular matrix stiffness mediates uterine repair via the Rap1a/ARHGAP35/RhoA/F-actin/YAP axis

Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity

Geranylgeranyl Isoprenoids and Hepatic Rap1a Regulate Basal and Statin-Induced Expression of PCSK9

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