RESUMO
Ferritin is known to be involved in numerous physiological roles, such as iron storage, as well as various pathological conditions and in generalized inflammatory states. Hyperferritinemia is also encountered in the setting of hemophagocytic lymphohistiocytosis (HLH). Current diagnostic criteria exist to define HLH based on several clinical and biochemical markers, including the serum ferritin level. In this study, we retrospectively evaluated the value of ferritin >500 ng/mL in diagnosing HLH in 344 consecutive patients admitted to the medical intensive care unit at our hospital. Nine cases of HLH were identified. Comparison of the HLH with the non-HLH group showed that their maximum median serum ferritin level was 25,652 (range 1977-100,727 ng/mL) versus 1180 (503-85,168 ng/mL) (P < 0.001), platelets were 30 (5-92 × 10(3)/µL) versus 113 (0-507 × 10(3)/µL) (P < 0.001), absolute neutrophil counts were 2.56 (0.02-23.7 × 10(3)/µL) versus 7.7 (0.01-82.7 × 10(3)/µL) (P = 0.002), and triglycerides were 255 (156-394 mg/dL) versus 127 (17-624 mg/dL) (P = 0.002), respectively. Using a receiver operating characteristic curve, the optimal maximum serum ferritin level for the diagnosis of HLH was 3951 ng/mL, exceeding the current diagnostic cutoff set forth in the HLH-2004 guidelines. These data suggest that a higher cutoff value of ferritin level may have improved utility in the diagnosis of secondary HLH in the critical care setting.
Assuntos
Cuidados Críticos , Ferritinas/sangue , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
ATP-binding cassette transporter D2 (D2) is an ABC half transporter that is thought to promote the transport of very long-chain fatty acyl-CoAs into peroxisomes. Both D2 and peroxisomes increase during adipogenesis. Although peroxisomes are essential to both catabolic and anabolic lipid metabolism, their function, and that of D2, in adipose tissues remain largely unknown. Here, we investigated the D2 localization and the proteome of D2-containing organelles, in adipose tissue. Centrifugation of mouse adipose homogenates generated a fraction enriched with D2, but deficient in peroxisome markers including catalase, PEX19, and ABCD3 (D3). Electron microscopic imaging of this fraction confirmed the presence of D2 protein on an organelle with a dense matrix and a diameter of â¼ 200 nm, the typical structure and size of a microperoxisome. D2 and PEX19 antibodies recognized distinct structures in mouse adipose. Immunoisolation of the D2-containing compartment confirmed the scarcity of PEX19 and proteomic profiling revealed the presence of proteins associated with peroxisome, endoplasmic reticulum (ER), and mitochondria. D2 is localized to a distinct class of peroxisomes that lack many peroxisome proteins, and may associate physically with mitochondria and the ER.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/metabolismo , Peroxissomos/metabolismo , Subfamília D de Transportador de Cassetes de Ligação de ATP , Animais , Retículo Endoplasmático/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Proteoma/metabolismo , Proteômica , Transdução de SinaisRESUMO
OBJECTIVE: Recent studies support a role for cholesterol in the development of obesity and nonalcoholic fatty liver disease. Mice lacking the ABCG5 ABCG8 (G5G8) sterol transporter have reduced biliary cholesterol secretion and are more susceptible to steatosis, hepatic insulin resistance, and loss of glycemic control when challenged with a high-fat diet. We hypothesized that accelerating G5G8-mediated biliary cholesterol secretion would correct these phenotypes in obese mice. APPROACH AND RESULTS: Obese (db/db) male and their lean littermates were administered a cocktail of control adenovirus or adenoviral vectors encoding ABCG5 and ABCG8 (AdG5G8). Three days after viral administration, measures of lipid and glucose homeostasis were determined, and tissues were collected for biochemical analyses. AdG5G8 increased biliary cholesterol and fecal sterol elimination. Fasting glucose and triglycerides declined, and glucose tolerance improved in obese mice expressing G5G8 compared with mice receiving control adenovirus. These changes were associated with a reduction in phosphorylated eukaryotic initiation factor 2α and c-Jun N-terminal kinase in liver, suggesting alleviation of endoplasmic reticulum stress. Phosphorylated insulin receptor and protein kinase B were increased, indicating restored hepatic insulin signaling. However, there was no reduction in hepatic triglycerides after the 3-day treatment period. CONCLUSIONS: Accelerating biliary cholesterol secretion restores glycemic control and reduces plasma triglycerides in obese db/db mice.