Showing papers by "Clay F. Semenkovich published in 2008"
TL;DR: Current thinking that is shaping molecular understanding of insulin resistance and atherosclerosis is addressed, and promising drugs such as the thiazolidinediones have come under scrutiny for possible deleterious CV effects.
172 citations
TL;DR: The results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages.
Abstract: Niemann-Pick C1 (NPC1) is a key participant in cellular cholesterol trafficking. Loss of NPC1 function leads to defective suppression of SREBP-dependent gene expression and failure to appropriately activate liver X receptor-mediated (LXR-mediated) pathways, ultimately resulting in intracellular cholesterol accumulation. To determine whether NPC1 contributes to regulation of macrophage sterol homeostasis in vivo, we examined the effect of NPC1 deletion in BM-derived cells on atherosclerotic lesion development in the Ldlr-/- mouse model of atherosclerosis. High-fat diet-fed chimeric Npc1-/- mice reconstituted with Ldlr-/-Npc1-/- macrophages exhibited accelerated atherosclerosis despite lower serum cholesterol compared with mice reconstituted with wild-type macrophages. The discordance between the low serum lipoprotein levels and the presence of aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the chimeric Npc1-/- mice played a greater role in atherosclerotic lesion formation than did serum lipoprotein levels. Macrophages from chimeric Npc1-/- mice showed decreased synthesis of 27-hydroxycholesterol (27-HC), an endogenous LXR ligand; decreased expression of LXR-regulated cholesterol transporters; and impaired cholesterol efflux. Lower 27-HC levels were associated with elevated cholesterol oxidation products in macrophages and plasma of chimeric Npc1-/- mice and with increased oxidative stress. Our results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages.
116 citations
TL;DR: Although hepatic TG content is widely variable and increases during liver regeneration, alterations in neither exogenous or endogenous lipid metabolic pathways, demonstrated to promote or diminish hepatic steatosis, influence hepatocyte proliferation.
108 citations
TL;DR: SMC p38α MAPK activation is required for neointima formation, perhaps because of its ability to promote retinoblastoma protein phosphorylation and minichromosome maintenance protein 6 expression.
Abstract: Background— Angioplasty and stent delivery are performed to treat atherosclerotic vascular disease but often cause deleterious neointimal lesion formation. Previously, growth factor receptor-bound protein 2 (Grb2), an intracellular linker protein, was shown to be essential for neointima formation and for p38 mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells (SMCs). In this study, the role of vascular SMC p38α MAPK in neointimal development was examined. Methods and Results— Compound transgenic mice were generated with doxycycline-inducible SMC-specific expression of dominant-negative p38α MAPK (DN-p38α). Doxycycline treatment resulted in the expression of DN-p38α mRNA and protein in transgenic arteries. Doxycycline-treated compound transgenic mice were resistant to neointima formation 21 days after carotid injury and showed reduced arterial p38 MAPK activation. To explore the mechanism by which p38α MAPK promotes neointima formation, an in vitro SMC culture system was used...
36 citations
TL;DR: Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate β-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic β- cell to establish a template for hyperfunction in early life and β-cells failure with age.
Abstract: OBJECTIVE— Low birth weight is associated with diabetes in adult life. Accelerated or “catch-up” postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine β-cell–specific programming or by altered metabolism associated with catch-up growth is unknown. RESEARCH DESIGN AND METHODS— We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 year of age. RESULTS— FASDEL mice did not manifest catch-up growth or insulin resistance. β-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but β-cell failure and diabetes occurred with age. FASDEL β-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because β-cell mass was increased in utero in FASDEL mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized β-cell mass in utero. CONCLUSIONS— Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate β-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic β-cell to establish a template for hyperfunction in early life and β-cell failure with age.
25 citations
Journal Article•
TL;DR: Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate p-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic p- cell to establish a template for hyperfunction in early life and p-cells failure with age.
Abstract: OBJECTIVE-Low birth weight is associated with diabetes in adult life. Accelerated or "catch-up" postnatal growth in response to small birth size is thought to presage disease years later. Whether adult disease is caused by intrauterine β-cell-specific programming or by altered metabolism associated with catch-up growth is unknown. RESEARCH DESIGN AND METHODS-We generated a new model of intrauterine growth restriction due to fatty acid synthase (FAS) haploinsufficiency (FAS deletion [FASDEL]). Developmental programming of diabetes in these mice was assessed from in utero to 1 year of age. RESULTS-FASDEL mice did not manifest catch-up growth or insulin resistance. p-Cell mass and insulin secretion were strikingly increased in young FASDEL mice, but p-cell failure and diabetes occurred with age. FASDEL β-cells had altered proliferative and apoptotic responses to the common stress of a high-fat diet. This sequence appeared to be developmentally entrained because p-cell mass was increased in utero in FASDEL mice and in another model of intrauterine growth restriction caused by ectopic expression of uncoupling protein-1. Increasing intrauterine growth in FASDEL mice by supplementing caloric intake of pregnant dams normalized p-cell mass in utero. CONCLUSIONS-Decreased intrauterine body size, independent of postnatal growth and insulin resistance, appears to regulate p-cell mass, suggesting that developing body size might represent a physiological signal that is integrated through the pancreatic p-cell to establish a template for hyperfunction in early life and p-cell failure with age.
1 citations