ABSTRACT
Lipopolysaccharides (LPS) of the cell wall of gram-negative bacteria trigger inflammation, which is associated with marked changes in glucose metabolism. Hyperglycemia is frequently observed during bacterial infection and it is a marker of a poor clinical outcome in critically ill patients. The aim of the current study was to investigate the effect of an acute injection or continuous infusion of LPS on experimentally induced hyperglycemia in wild-type and genetically engineered mice. The acute injection of a single dose of LPS produced an increase in glucose disposal and glucose-stimulated insulin secretion (GSIS). Continuous infusion of LPS through mini-osmotic pumps was also associated with increased GSIS. Finally, manipulation of LPS detoxification by knocking out the plasma phospholipid transfer protein (PLTP) led to increased glucose disposal and GSIS. Overall, glucose tolerance and GSIS tests supported the hypothesis that mice treated with LPS develop glucose-induced hyperinsulinemia. The effects of LPS on glucose metabolism were significantly altered as a result of either the accumulation or antagonism of glucagon-like peptide 1 (GLP-1). Complementary studies in wild-type and GLP-1 receptor knockout mice further implicated the GLP-1 receptor-dependent pathway in mediating the LPS-mediated changes in glucose metabolism. Hence, enhanced GLP-1 secretion and action underlies the development of glucose-mediated hyperinsulinemia associated with endotoxemia.
Subject(s)
Glucagon-Like Peptide 1/metabolism , Glucose/metabolism , Insulin/metabolism , Lipopolysaccharides/toxicity , Receptors, Glucagon/metabolism , Animals , Blood Glucose , Glucagon-Like Peptide 1/genetics , Glucagon-Like Peptide-1 Receptor , Lipopolysaccharides/metabolism , Mice , Mice, Knockout , Phospholipid Transfer Proteins/genetics , Phospholipid Transfer Proteins/metabolism , Receptors, Glucagon/geneticsABSTRACT
OBJECTIVE: Cholesteryl ester transfer protein (CETP) is a target gene for the liver X receptor (LXR). The aim of this study was to further explore this regulation in the monocyte-macrophage lineage and its modulation by lipid loading and inflammation, which are key steps in the process of atherogenesis. METHODS AND RESULTS: Exposure of bone marrow-derived macrophages from human CETP transgenic mice to the T0901317 LXR agonist increased CETP, PLTP, and ABCA1 mRNA levels. T0901317 also markedly increased CETP mRNA levels and CETP production in human differentiated macrophages, whereas it had no effect on CETP expression in human peripheral blood monocytes. In inflammatory mouse and human macrophages, LXR-mediated CETP gene upregulation was inhibited, even though ABCA1, ABCG1, and SREBP1c inductions were maintained. The inhibition of CETP gene response to LXR agonists in inflammatory cells was independent of lipid loading (ie, oxidized LDL increased CETP production in noninflammatory macrophages with a synergistic effect of synthetic LXR agonists). CONCLUSIONS: LXR-mediated induction of human CETP expression is switched on during monocyte-to-macrophage differentiation, is magnified by lipid loading, and is selectively lost in inflammatory macrophages, which suggests that inflammatory cells may not increase the circulating CETP pool on LXR agonist treatment.
