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Articles by L Qian
Total Records ( 4 ) for L Qian
  D Qi , K Cai , O Wang , Z Li , J Chen , B Deng , L Qian and Y. Le
 

Amylin is the major component of pancreatic amyloid, which is implicated in the development of type 2 diabetes. It is costored with insulin in the secretory granules of pancreatic β-cells and cosecreted with insulin following stimulation with glucose. Here, we investigate the effect of fatty acids (FAs) on amylin expression and secretion by β-cells and explore the underlying mechanisms. Palmitate and oleate dose-dependently induced amylin mRNA accumulation in murine pancreatic β-cell line MIN6 and primary pancreatic islets. the inductive effect of FAs on amylin expression is independent of glucose concentration. FAs upregulated amylin expression at the transcriptional level, and FAs must be metabolized to induce amylin expression. FAs also significantly induced human amylin promoter activation. Pretreatment of MIN6 cells with Ca2+ chelator (EGTA, BAPTA-AM) PKC inhibitor Gö-6976 or protein synthesis inhibitor cycloheximide significantly inhibited FA-induced amylin mRNA expression. Transcription factors cAMP-responsive element-binding protein, pancreatic and duodenal homeobox factor-1, and peroxisome proliferator-activated receptor were not involved in FA-induced amylin expression. Palmitate and oleate both increased amylin and insulin release from MIN6 cells and stimulated amylin expression but had no effect on insulin expression. Mice refed with Intralipid had significantly higher levels of plasma FFA, amylin, and insulin than those refed with saline. These data demonstrate that FAs differently regulate amylin and insulin expression and induce both amylin and insulin release. Ca2+ and PKC signaling pathways and de novo-synthesized protein(s) were involved in FA-induced amylin expression. Induction of amylin production and release by FA may contribute to its biological functions under physiological conditions.

  S Wang , L Qian and R. J. Carroll
 

Efficient estimation of parameters is a major objective in analyzing longitudinal data. We propose two generalized empirical likelihood-based methods that take into consideration within-subject correlations. A nonparametric version of the Wilks theorem for the limiting distributions of the empirical likelihood ratios is derived. It is shown that one of the proposed methods is locally efficient among a class of within-subject variance-covariance matrices. A simulation study is conducted to investigate the finite sample properties of the proposed methods and compares them with the block empirical likelihood method by You et al. (2006) and the normal approximation with a correctly estimated variance-covariance. The results suggest that the proposed methods are generally more efficient than existing methods that ignore the correlation structure, and are better in coverage compared to the normal approximation with correctly specified within-subject correlation. An application illustrating our methods and supporting the simulation study results is presented.

  H Gudmundsson , T. J Hund , P. J Wright , C. F Kline , J. S Snyder , L Qian , O. M Koval , S. R Cunha , M George , M. A Rainey , F. E Kashef , W Dun , P. A Boyden , M. E Anderson , H Band and P. J. Mohler
 

Rationale: Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules. Membrane protein dynamics in health and disease are maintained by a complex ensemble of intracellular targeting, scaffolding, recycling, and degradation pathways. Surprisingly, despite decades of research linking dysfunction in membrane protein trafficking with human cardiovascular disease, essentially nothing is known regarding the molecular identity or function of these intracellular targeting pathways in excitable cardiomyocytes.

Objective: We sought to discover novel pathways for membrane protein targeting in primary cardiomyocytes.

Methods and Results: We report the initial characterization of a large family of membrane trafficking proteins in human heart. We used a tissue-wide screen for novel ankyrin-associated trafficking proteins and identified 4 members of a unique Eps15 homology (EH) domain–containing protein family (EHD1, EHD2, EHD3, EHD4) that serve critical roles in endosome-based membrane protein targeting in other cell types. We show that EHD1-4 directly associate with ankyrin, provide the first information on the expression and localization of these molecules in primary cardiomyocytes, and demonstrate that EHD1-4 are coexpressed with ankyrin-B in the myocyte perinuclear region. Notably, the expression of multiple EHD proteins is increased in animal models lacking ankyrin-B, and EHD3-deficient cardiomyocytes display aberrant ankyrin-B localization and selective loss of Na/Ca exchanger expression and function. Finally, we report significant modulation of EHD expression following myocardial infarction, suggesting that these proteins may play a key role in regulating membrane excitability in normal and diseased heart.

Conclusions: Our findings identify and characterize a new class of cardiac trafficking proteins, define the first group of proteins associated with the ankyrin-based targeting network, and identify potential new targets to modulate membrane excitability in disease. Notably, these data provide the first link between EHD proteins and a human disease model.

  L Qian , V Lopez , Y. A Seo and S. L. Kelleher
 

The zinc transporter ZnT2 (SLC30A2) plays an important role in zinc secretion into milk during lactation. The physiological process of mammary gland secretion is regulated through complex integration of multiple lactogenic hormones. Prolactin plays a primary role in this regulation through the activation of various signaling cascades including Jak2/STAT5, mitogen-activated protein kinase (MAPK), p38, and phosphatidylinositol 3-kinase (PI3K). The precise mechanisms that regulate the transfer of specific nutrients such as zinc into milk are not well understood. Herein we report that prolactin increased ZnT2 abundance transcriptionally in cultured mammary epithelial (HC11) cells. To delineate the responsible mechanisms, we first determined that prolactin-mediated ZnT2 induction was inhibited by pretreatment with the Jak2 inhibitor AG490 but not by the MAPK inhibitor PD-98059. Using a luciferase reporter assay, we demonstrated that ZnT2 promoter activity was increased by prolactin treatment, which was subsequently abolished by expression of a dominant-negative STAT5 construct, implicating the Jak2/STAT5 signaling pathway in the transcriptional regulation of ZnT2. Two putative consensus STAT5 binding sequences in the ZnT2 promoter were identified (GAS1:–674 to –665 and GAS2:–377 to –368). Mutagenesis of the proximal GAS2 element resulted in complete abrogation of PRL-induced ZnT2 promoter activity. The promoter incorporating the distal GAS1 mutation was only able to respond to very high PRL concentrations. Results from both the mutagenesis and gel shift assays indicated that a cooperative relationship exists between GAS1 and GAS2 for PRL-induced activation; however, the proximal GAS2 plays a more critical role in STAT5-mediated signal transduction compared with the GAS1 element. Finally, chromosome immunoprecipition assay further confirmed that prolactin activates STAT5 binding to the ZnT2 promoter in vivo. Taken together, these results illustrate that prolactin regulates the transcription of ZnT2 through activation of the Jak2/STAT5 signaling pathway to assist in providing optimal zinc for secretion into milk during lactation.

 
 
 
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