Efficient engulfment of the intact cell corpse is a critical end point of apoptosis, required to prevent secondary necrosis and inflammation. The presentation of "eat-me" signals on the dying cell is an important part of this process of recognition and engulfment by professional phagocytes. Here, we present evidence that apoptotic cells secrete chemotactic factor(s) that stimulate the attraction of monocytic cells and primary macrophages. The activation of caspase-3 in the apoptotic cell was found to be required for the release of this chemotactic factor(s). The putative chemoattractant was identified as the phospholipid, lysophosphatidylcholine. Further analysis showed that lysophosphatidylcholine was released from apoptotic cells due to the caspase-3 mediated activation of the calcium-independent phospholipase A(2). These data suggest that in addition to eat-me signals, apoptotic cells display attraction signals to ensure the efficient removal of apoptotic cells and prevent postapoptotic necrosis.

OBJECTIVE -The ␣ 2 -Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver.RESEARCH DESIGN AND METHODS -Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by 1 H magnetic resonance spectroscopy.RESULTS -AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P ϭ 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r ϭ Ϫ0.22, P ϭ 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r ϭ 0.27, P ϭ 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P ϭ 0.02).CONCLUSIONS -We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance. Diabetes Care 29:853-857, 2006I nsulin resistance plays a crucial role in the development of type 2 diabetes (1). Multiple mechanisms are thought to be involved in its pathogenesis. Among them, the human ␣ 2 -Heremans-Schmid glycoprotein (AHSG) was found to be important in animals and in in vitro studies. It is an abundant serum protein in mammals. Bovine and murine fetuin-A and pp63 in rats are homologues of AHSG (2,3). In humans, except for the tongue and the placenta, it is exclusively expressed in the liver (4). It is a natural inhibitor of the insulin-stimulated insulin receptor tyrosine kinase (3). Acute injection of human recombinant AHSG inhibi t e d i n s u l i n -s t i m u l a t e d t y r o s i n e phosphorylation of the insulin receptor and insulin receptor substrate-1 in rat liver and skeletal muscle (3). In addition, AHSG knockout mice display improved insulin sensitivity and are resistant to weight gain on a high-fat diet (5).While these data reflect that AHSG is an important candidate among the factors that induce insulin resistance, the role of this protein in the natural history of type 2 diabetes is still unclear (6). Recent reports from genetic studies suggest that single nucleotide polymor...

De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.

Cardiorespiratory fitness, independently of total adiposity, body fat distribution and exercise intensity, determines liver fat content in humans, suggesting that fitness and liver fat are causally related to each other. Moreover, measurement of fitness at baseline predicts the effectiveness of a lifestyle intervention in reducing hepatic steatosis in patients with NAFLD.

Considering the "semimalignant" character of this entity and the poor treatment results in patients with recurrent tumors, marginal or wide resection for primary treatment is recommended. The superior imaging quality of MRI greatly facilitates preoperative planning.

Immunoreactivity with HMB-45 has recently been described in renal angiomyolipoma, a tumour of smooth muscle cells. HMB-45 is a monoclonal antibody that reacts specifically with melanosomes. In order to determine whether the tumour cells contain melanosomes and synthesize melanin, seven tumours were studied by light microscopy and immunohistochemically with the antibodies HMB-45, KP1 (CD68), PG-M1 (CD68), Ki-M1P, anti-lysozyme, anti-smooth-muscle actin, anti-vimentin, anti-S100 protein and KL1 (anti-keratin). Two tumours were also studied by electronmicroscopy and one by immuno-electronmicroscopy. Histochemical investigation for dopa oxidase was performed on cryostat sections. The tumours contained varying numbers of HMB-45-positive muscle cells. Reactivity was noted in lysosomal granules and rough endoplasmic reticulum. Typical premelanosomes were found in the tumour cells by electronmicroscopy. Groups of tumour cells stained for dopa oxidase. The tumour cells were not reactive for lysozyme, but reacted with KP1, PG-M1 and Ki-M1P. Immuno-electronmicroscopy showed that reactivity for KP1 was located within lysosomal granules. The findings show that the tumour cells of renal angiomyolipoma contain premelanosomes and that they are able to synthesize melanin, because they contain dopa oxidase. Immunoreactivity with KP1, PG-M1 and Ki-M1P can be attributed, in the absence of staining for lysozyme, to the large number of lysosomal granules. The tumour cells were not found to be related to macrophages or myeloid cells.

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OBJECTIVEThe nitric oxide/cGMP/cGMP-dependent protein kinase type I (cGKI) signaling pathway regulates cell functions that play a pivotal role in the pathogenesis of type 2 diabetes. However, the impact of a dysfunction of this pathway for glucose metabolism in vivo is unknown.RESEARCH DESIGN AND METHODSThe expression of cGKI in tissues relevant to insulin action was analyzed by immunohistochemistry. The metabolic consequences of a genetic deletion of cGKI were studied in mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice).RESULTSIn wild-type mice, cGKI protein was detected in hepatic stellate cells, but not in hepatocytes, skeletal muscle, fat cells, or pancreatic β-cells. Compared with control animals, cGKI-SM mice had higher energy expenditure in the light phase associated with lower body weight and fat mass and increased insulin sensitivity. Mutant mice also showed higher fasting glucose levels, whereas insulin levels and intraperitoneal glucose tolerance test results were similar to those in control animals. Interleukin (IL)-6 signaling was strongly activated in the liver of cGKI-SM mice as demonstrated by increased levels of IL-6, phospho-signal transducer and activator of transcription 3 (Tyr 705), suppressor of cytokine signaling-3, and serum amyloid A2. Insulin-stimulated tyrosine phosphorylation of the insulin receptor in the liver was impaired in cGKI-SM mice. The fraction of Mac-2–positive macrophages in the liver was significantly higher in cGKI-SM mice than in control mice. In contrast with cGKI-SM mice, conditional knockout mice lacking cGKI only in the nervous system were normal with respect to body weight, energy expenditure, fasting glucose, IL-6, and insulin action in the liver.CONCLUSIONSGenetic deletion of cGKI in non-neuronal cells results in a complex metabolic phenotype, including liver inflammation and fasting hyperglycemia. Loss of cGKI in hepatic stellate cells may affect liver metabolism via a paracrine mechanism that involves enhanced macrophage infiltration and IL-6 signaling.