Pharmacological inhibition of diacylglycerol acyltransferase-1 and insights into postprandial gut peptide secretion.

Aim: To examine the role that enzyme Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) plays in postprandial gut peptide secretion and signaling.

Methods: The standard experimental paradigm utilized to evaluate the incretin response was a lipid challenge. Following a lipid challenge, plasma was collected cardiac puncture at each time point from a cohort of 5-8 mice per group from baseline at time zero to 10 h.

Selective Activation of AMPK 1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the 1 subunit.

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans.

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG.

A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells.

Mechanical forces are critical for fetal lung development. Using surfactant protein C (SP-C) as a marker, we previously showed that stretch-induced fetal type II cell differentiation is mediated via the ERK pathway. Caveolin-1, a major component of the plasma membrane microdomains, is important as a signaling protein in blood vessels exposed to shear stress.

Mechanical stretch promotes fetal type II epithelial cell differentiation via shedding of HB-EGF and TGF-alpha.

The mechanisms by which mechanical forces promote fetal lung development are not fully understood. Here, we investigated differentiation of fetal type II epithelial cells via the epidermal growth factor receptor (EGFR) in response to mechanical strain. First, we showed that incubation of embryonic day (E) 19 fetal type II cells with recombinant heparin-binding EGF-like growth factor (HB-EGF) or transforming growth factor (TGF)-alpha, but not with amphiregulin (AR), betacellulin (BTC) or epiregulin (EPR), increased fetal type II cell differentiation, as measured by surfactant protein B/C mRNA and protein levels.

Roles of RhoA and Rac1 on actin remodeling and cell alignment and differentiation in fetal type II epithelial cells exposed to cyclic mechanical stretch.

Mechanical forces are critical for normal fetal lung development. However, the signaling events that promote lung maturation are not fully understood. In this study, the authors analyzed the role of Rho family guanidine triphosphatases (GTPases) in isolated embryonic day 19 (E19) fetal type II epithelial cells exposed to 5% cyclic stretch.

Interleukin-10 protects cultured fetal rat type II epithelial cells from injury induced by mechanical stretch.

Mechanical ventilation plays a central role in the pathogenesis of bronchopulmonary dysplasia. However, the mechanisms by which excessive stretch of fetal or neonatal type II epithelial cells contributes to lung injury are not well defined. In these investigations, isolated embryonic day 19 fetal rat type II epithelial cells were cultured on substrates coated with fibronectin and exposed to 5% or 20% cyclic stretch to simulate mechanical forces during lung development or lung injury, respectively.

DNA microarray reveals novel genes induced by mechanical forces in fetal lung type II epithelial cells.

Mechanical forces are essential for normal fetal lung development. However, the cellular and molecular mechanisms regulating this process are still poorly defined. In this study, we used oligonucleotide microarrays to investigate gene expression in cultured embryonic d 19 rat fetal lung type II epithelial cells exposed to a level of mechanical strain similar to the developing lung.

Strain-induced fetal type II epithelial cell differentiation is mediated via cAMP-PKA-dependent signaling pathway.

The signaling pathways by which mechanical forces modulate fetal lung development remain largely unknown. In the present study, we tested the hypothesis that strain-induced fetal type II cell differentiation is mediated via the cAMP signaling pathway. Freshly isolated E19 fetal type II epithelial cells were cultured on collagen-coated silastic membranes and exposed to mechanical strain for varying intervals, to simulate mechanical forces during lung development.