Youfei Guan

FAM3A activates PI3K p110α/Akt signaling to ameliorate hepatic gluconeogenesis and lipogenesis

FAM3A belongs to a novel cytokine‐like gene family, and its physiological role remains largely unknown. In our study, we found a marked reduction of FAM3A expression in the livers of db/db and high‐fat diet (HFD)‐induced diabetic mice. Hepatic overexpression of FAM3A markedly attenuated hyperglycemia, insulin resistance, and fatty liver with increased Akt (pAkt) signaling and repressed gluconeogenesis and lipogenesis in the livers of those mice. In contrast, small interfering RNA (siRNA)‐mediated knockdown of hepatic FAM3A resulted in hyperglycemia with reduced pAkt levels and increased gluconeogenesis and lipogenesis in the livers of C57BL/6 mice. In vitro study revealed that FAM3A was mainly localized in the mitochondria, where it increases adenosine triphosphate (ATP) production and secretion in cultured hepatocytes. FAM3A activated Akt through the p110α catalytic subunit of PI3K in an insulin‐independent manner. Blockade of P2 ATP receptors or downstream phospholipase C (PLC) and IP3R and removal of medium calcium all significantly reduced FAM3A‐induced increase in cytosolic free Ca2+ levels and attenuated FAM3A‐mediated PI3K/Akt activation. Moreover, FAM3A‐induced Akt activation was completely abolished by the inhibition of calmodulin (CaM). Conclusion: FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PI3K‐Akt signaling pathway by way of a Ca2+/CaM‐dependent mechanism. Up‐regulating hepatic FAM3A expression may represent an attractive means for the treatment of insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). (Hepatology 2014;59:1779–1790)

Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRα-SREBP1c-dependent mechanism.

Liver X receptors (LXRs) including LXRα and LXRβ are members of the nuclear hormone receptor superfamily of ligand activated transcription factors, which serve as lipid sensors to regulate expression of genes controlling many aspects of cholesterol and fatty acid metabolism. The liver is the central organ in controlling lipid metabolism. In the present study, we aimed at elucidating the role of LXR activation in hepatic fatty acid homeostasis.

Glucagon‐like peptide 1‐potentiated insulin secretion and proliferation of pancreatic β‐cells GLP‐1促进胰岛素分泌和胰岛β细胞增殖的机制

Glucagon‐like peptide‐1 (GLP‐1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β‐cells. GLP‐1 exerts its effects by binding to its G‐protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β‐cells. In addition to its insulinotropic effects, GLP‐1 also preserves pancreatic β‐cell mass by stimulating β‐cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP‐1 is affected by and interplays with glucose levels. Due to such advantages, GLP‐1‐based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP‐1 potentiates diminished glucose‐stimulated insulin secretion and β‐cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP‐1 in regulation of insulin secretion and pancreatic β‐cell proliferation.

Glucagon-like peptide 1-potentiated insulin secretion and proliferation of pancreatic β-cells.

Glucagon‐like peptide‐1 (GLP‐1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β‐cells. GLP‐1 exerts its effects by binding to its G‐protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β‐cells. In addition to its insulinotropic effects, GLP‐1 also preserves pancreatic β‐cell mass by stimulating β‐cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP‐1 is affected by and interplays with glucose levels. Due to such advantages, GLP‐1‐based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP‐1 potentiates diminished glucose‐stimulated insulin secretion and β‐cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP‐1 in regulation of insulin secretion and pancreatic β‐cell proliferation.

Glucotoxicity inhibits cAMP-protein kinase A-potentiated glucose-stimulated insulin secretion in pancreatic β-cells.

The effect of incretin is markedly blunted in patients with type 2 diabetes (T2D), and this reduced effect of incretin is correlated with a diminished insulintropic potency of glucagon‐like peptide‐1 (GLP‐1). We reported recently that GLP‐1 potentiates glucose‐stimulated insulin secretion (GSIS) mainly via activation of the cAMP–protein kinase A (PKA) signaling pathway in INS‐1E cells under hyperglycemic conditions. In the present study, we further explored whether glucotoxicity impairs cAMP–PKA‐mediated effects and its relevance to the reduced insulinotropic action of GLP‐1 in hyperglycemia.

Glucotoxicity inhibits cAMP–protein kinase A-potentiated glucose-stimulated insulin secretion in pancreatic β-cells葡萄糖毒性抑制cAMP-PKA通路促进的胰岛β细胞中血糖刺激的胰岛素分泌

The effect of incretin is markedly blunted in patients with type 2 diabetes (T2D), and this reduced effect of incretin is correlated with a diminished insulintropic potency of glucagon‐like peptide‐1 (GLP‐1). We reported recently that GLP‐1 potentiates glucose‐stimulated insulin secretion (GSIS) mainly via activation of the cAMP–protein kinase A (PKA) signaling pathway in INS‐1E cells under hyperglycemic conditions. In the present study, we further explored whether glucotoxicity impairs cAMP–PKA‐mediated effects and its relevance to the reduced insulinotropic action of GLP‐1 in hyperglycemia.

Induction of cytochrome P450 4A14 contributes to angiotensin II-induced renal fibrosis in mice

Angiotensin II (AngII) plays an important role in the pathogenesis of hypertension and associated renal injuries. To elucidate the molecular mechanism by which AngII induces renal damage, we found that AngII infusion significantly induced CYP4A14 expression in renal proximal tubule cells (RPTCs) with marked increases in blood pressure and proteinuria. Renal production of the major CYP4A metabolite, 20-HETE, was also significantly increased in the AngII-treated mice. Compared to wild-type (WT) mice, CYP4A14 knockout (CYP4A14-/-) mice exhibited significantly lower levels of blood pressure, renal 20-HETE production, proteinuria and renal fibrosis following AngII infusion. Furthermore, AngII-induced renal expression of profibrotic genes and proinflammatory genes was significantly attenuated in CYP4A14-/- mice. In vitro studies using cultured RPTCs demonstrated that AngII significantly induced CYP4A14 expression and 20-HETE production via the MAPK signaling pathway. AngII treatment increased TGF-β and collagen expression, which was attenuated by the CYP4A inhibitor, TS-011. Moreover, 20-HETE treatment potently induced CYP4A14 expression and TGF-β and collagen levels. Collectively, these findings suggest that attenuated renal fibrosis in AngII-treated CYP4A14-/- mice may result from both reduced systemic blood pressure and renal 20-HETE production. Therefore, CYP4A14 may represent a useful target for the treatment of AngII-associated renal damage.

Human antigen R: A novel therapeutic target for diabetic nephropathy? 人抗原R（HuR）: 糖尿病肾病新的治疗靶点？

The prevalence of diabetes among adults has reached 6.4% worldwide and 11.6% in China. As the leading cause of end-stage renal disease (ESRD), diabetic renal complications, or diabetic nephropathy (DN), has become a very serious public health concern. DN is characterized by sequential pathophysiological events, including glomerular hypertrophy, mesangial expansion, thickening of glomerular basement membrane, podocyte loss and foot process effacement, and tubulointerstitial fibrosis due to accumulation of extracelluar matrix (ECM) proteins. Endothelial dysfunction and inflammation mediated by infiltrating macrophages are also involved in the pathogenesis of DN. DN is generally believed to be the result of complex interactions between metabolic and hemodynamic factors. High glucose (HG) increases the generation of advanced glycation end products (AGEs) and the levels of growth factors, especially transforming growth factor β1 (TGF-β1) and connective growth factor (CTGF), two fibrogenic factors in renal tissue. Multiple signal transduction mechanisms and kinases including oxidant stress, gluco-and lipotoxicity, protein kinase C, Akt kinase, receptor and nonreceptor protein tyrosine kinases have been implicated in the development of DN, activating key effectors, such as Smads and NF-κB, and growth factors leading to increased expression of pro-inflammatory cytokines, cell cycle genes, profibrotic and ECM genes involved in DN. The key pathological change in DN is renal fibrosis, including glomerulosclerosis and tubulointerstitial fibrosis. Increasing evidence indicates that tubular epithelialmesenchymal transition (EMT) plays a critical role in these processes. EMT manifests a phenotypical change through which epithelial cells lose their epithelial characteristics and transition into mesenchymal/myofibroblast cells. The resultant morphological changes occur with the loss of epithelial cell adhesion molecules, such as E-cadherin and cytokeratin; the appearance of the mesenchymal markers, including α-SMA and vimentin; and cytoskeletal remodeling, resulting in glomerular and tubular structural disruption. In these processes, many factors, in particular TGF-β1 and CTGF, trigger EMT, while repression of the transcription factors Snail and c-fos is important for the maintenance of epithelial morphology. Recently, the importance of epigenetic mechanisms in DN has attracted great attention. At the posttranscriptional level, gene expression is regulated by two major types of transbinding factors, i.e. microRNAs (miRNAs) and RNA binding proteins (RBPs). miRNAs are a large group of small (19–23-nt-long) non-coding RNAs that can regulate gene expression at the posttranscriptional level mainly by blocking translation or promoting cleavage of their target mRNAs, playing roles in diverse biological processes and many diseases. In contrast, RBPs compose a vast group of structurally and functionally distinct proteins, which regulate mRNA stability and translation rate by interacting with target mRNAs via different RNA interaction motifs. RBPs are different from miRNAs in both structure and complexity and perform multiple functions regulating all aspects of RNA metabolism. Although the mechanisms are not completely the same, both miRNAs and RBPs interact with the 3′-untranslated region (UTR) of target mRNAs to modulate mRNA stability and translation. The human antigen R (HuR), which represents one of the best characterized RBPs, is an approximately 34 kD protein ubiquitously expressed and functionally involved in modulating the stability and translational efficiency of mRNAs by interacting with AUor U-rich sequence elements (ARE) in the 3′-UTR. A large body of evidence demonstrates that HuR is involved in the regulation of various cellular processes, including cell cycle regulation, stress response, cell apoptosis, and tumor development. In addition, HuR has been strongly implicated in the inflammatory process. In various cell types, HuR binds transcripts encoding inflammatory cytokines, such as IL-6, IL-8, TNF-α, TGF-β, and IFN-γ, and pro-inflammatory mediators, including COX-2 and iNOS, thus promoting the expression of these proteins. HuR has also been found to be involved in the fibrotic process and ECM remodeling. In renal mesangial cells, HuR has been shown to promote matrix metallopeptidase 9 (MMP-9) expression by stabilizing MMP-9 mRNA, resulting in remodeling of the extracellular matrix. However, whether HuR is also involved in renal fibrosis, especially EMTinduced renal fibrosis, remains unclear. In the present study, Yu et al. have reported an additional mechanism involved in the pathogenesis of DN, in which they showed that dysfunction of the RNA binding protein HuR may promote EMT process in diabetic bs_bs_banner

Glucotoxicity inhibits cAMP-protein kinase A-potentiated glucose-stimulated insulin secretion in pancreaticβ-cells葡萄糖毒性抑制cAMP-PKA通路促进的胰岛β细胞中血糖刺激的胰岛素分泌: Glucotoxicity blunts PKA-mediated action

The effect of incretin is markedly blunted in patients with type 2 diabetes (T2D), and this reduced effect of incretin is correlated with a diminished insulintropic potency of glucagon‐like peptide‐1 (GLP‐1). We reported recently that GLP‐1 potentiates glucose‐stimulated insulin secretion (GSIS) mainly via activation of the cAMP–protein kinase A (PKA) signaling pathway in INS‐1E cells under hyperglycemic conditions. In the present study, we further explored whether glucotoxicity impairs cAMP–PKA‐mediated effects and its relevance to the reduced insulinotropic action of GLP‐1 in hyperglycemia.

Glucagon-like peptide 1-potentiated insulin secretion and proliferation of pancreaticβ-cells GLP-1促进胰岛素分泌和胰岛β细胞增殖的机制: GLP-1 potentiatesβ-cell function

Glucagon‐like peptide‐1 (GLP‐1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β‐cells. GLP‐1 exerts its effects by binding to its G‐protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β‐cells. In addition to its insulinotropic effects, GLP‐1 also preserves pancreatic β‐cell mass by stimulating β‐cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP‐1 is affected by and interplays with glucose levels. Due to such advantages, GLP‐1‐based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP‐1 potentiates diminished glucose‐stimulated insulin secretion and β‐cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP‐1 in regulation of insulin secretion and pancreatic β‐cell proliferation.