27 research outputs found
Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins
Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling
Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-Ξ³
Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary
infection, establishes life-long persistence in all infected individuals. Acute
hCMV infections cause a variety of diseases in humans with developmental or
acquired immune deficits. In addition, persistent hCMV infection may contribute
to various chronic disease conditions even in immunologically normal people. The
pathogenesis of hCMV disease has been frequently linked to inflammatory host
immune responses triggered by virus-infected cells. Moreover, hCMV infection
activates numerous host genes many of which encode pro-inflammatory proteins.
However, little is known about the relative contributions of individual viral
gene products to these changes in cellular transcription. We systematically
analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major
transcriptional activator and antagonist of type I interferon (IFN) signaling,
on the human transcriptome. Following expression under conditions closely
mimicking the situation during productive infection, IE1 elicits a global type
II IFN-like host cell response. This response is dominated by the selective
up-regulation of immune stimulatory genes normally controlled by IFN-Ξ³ and
includes the synthesis and secretion of pro-inflammatory chemokines.
IE1-mediated induction of IFN-stimulated genes strictly depends on
tyrosine-phosphorylated signal transducer and activator of transcription 1
(STAT1) and correlates with the nuclear accumulation and sequence-specific
binding of STAT1 to IFN-Ξ³-responsive promoters. However, neither synthesis
nor secretion of IFN-Ξ³ or other IFNs seems to be required for the
IE1-dependent effects on cellular gene expression. Our results demonstrate that
a single hCMV protein can trigger a pro-inflammatory host transcriptional
response via an unexpected STAT1-dependent but IFN-independent mechanism and
identify IE1 as a candidate determinant of hCMV pathogenicity
Depression and health-related quality of life in people with coronary heart disease: a systematic review
Critical care nursing practice regarding patient anxiety assement and management
Anxiety is common in critically ill patients and can adversely affect recovery if not properly assessed and treated. The objectives of this study were to: (1) identify the clinical indicators that critical care nurses consider to be the defining attributes of anxiety in critically ill patients; and (2) delineate the interventions that critical care nurses use to alleviate anxiety in their patients. A total of 2500 nurses who worked in adult critical care areas were randomly selected from the membership of the American Association of Critical Care Nurses. Nurses selected were mailed a survey designed to determine what they considered to be the important attributes of anxiety in their patients and what interventions they commonly used to manage anxiety. The 593 nurses (31.6% response rate) who responded identified 70 individual anxiety indicators and 61 anxiety management strategies that were categorized into four and three major categories, respectively. The four major anxiety assessment categories were: (1) physical/physiological; (2) behavioral; (3) psychological/cognitive; and (4) social. The three major anxiety management strategies were: (1) care techniques; (2) improving knowledge and communication; and (3) support. Critical care nurses reported numerous and distinctive anxiety indicators and management strategies. Further research is needed to examine exactly how appropriate and effective these assessment indicators and management strategies are. Β© 2003 Elsevier Ltd. All rights reserved
Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake
The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD (n = 10) or chow control (CTR, n = 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ΞAUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by β30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0β90 min) and 2 (P2, 90β180 min). During P1, somatostatin, basal intraportal glucagon, 4 Γ basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mgΒ·kgβ1Β·minβ1). Net hepatic glucose uptake during P1 and P2 was β0.4 Β± 0.1 [output] and 0.2 Β± 0.8 mgΒ·kgβ1Β·minβ1 in the HFFD group, respectively, and 1.8 Β± 0.8 and 3.5 Β± 1.0 mgΒ·kgβ1Β·minβ1 in the CTR group, respectively (P < 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 Β± 0.2 and 1.5 Β± 0.4 mgΒ·kgβ1Β·minβ1 in the HFFD and CTR groups, respectively (P < 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis