Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis

Liver plays a central role in the biogenesis of major metabolites including glucose, fatty acids, and cholesterol. Increased incidence of obesity in the modern society promotes insulin resistance in the peripheral tissues in humans, and could cause severe metabolic disorders by inducing accumulation of lipid in the liver, resulting in the progression of non-alcoholic fatty liver disease (NAFLD). NAFLD, which is characterized by increased fat depots in the liver, could precede more severe diseases such as non-alcoholic steatohepatitis (NASH), cirrhosis, and in some cases hepatocellular carcinoma. Accumulation of lipid in the liver can be traced by increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, or the increased incidence of de novo lipogenesis. In this review, I would like to focus on the roles of individual pathways that contribute to the hepatic steatosis as a precursor for the NAFLD

Natural progress of D-dimer following total joint arthroplasty: a baseline for the diagnosis of the early postoperative infection

Background Early detection followed by prompt intervention is essential for the treatment of periprosthetic joint infection (PJI). D-dimer, a fibrin degradation product, characteristically changes rapidly during early postoperative period and has a short half-life. The aim of this prospective study was to measure postoperative change of D-dimer level after joint arthroplasty in conjunction with ESR and CRP. Methods ESR, CRP, and D-dimer levels were measured on the day before surgery, postoperative days 1, 2, 3, and 5 and weeks 2 and 6 in 65 patients who underwent elective primary total hip arthroplasty (38 hips in 38 patients) or total knee arthroplasty (27 knees in 27 patients). We compared perioperative changes of the three biomarkers. Results ESR level was elevated from postoperative day 1 and reached a peak level of 45 mm/h at postoperative day 5. The elevation persisted until postoperative week 6. CRP level was elevated from postoperative day 1 and reached a peak level of 10 mg/dl between postoperative day 2 and day 3. The CRP level was decreased to the normal level around postoperative week 2. D-dimer level was sharply elevated and peaked to 4.5 μg/dl at postoperative day 1. At postoperative day 2, it decreased to baseline level. After then, it slowly elevated again and reached a second peak at postoperative week 2. Conclusion D-dimer showed a more rapid rise and fall than ESR and CRP in very early postoperative period. The D-dimer test might be effective in early detection of PJI, if combined with levels of ESR and CRP. The postoperative change of D-dimer in our study can serve as a baseline for early diagnosis of PJI.This study was supported by Corentec (Cheonan, South Korea)

Identification of the tyrosine phosphatase PTP-MEG2 as an antagonist of hepatic insulin signaling

SummaryInsulin resistance is a primary defect in type 2 diabetes characterized by impaired peripheral glucose uptake and insufficient suppression of hepatic glucose output. Insulin signaling inhibits liver glucose production by inducing nuclear exclusion of the gluconeogenic transcription factor FOXO1 in an Akt-dependent manner. Through the concomitant application of genome-scale functional screening and quantitative image analysis, we have identified PTP-MEG2 as a modulator of insulin-dependent FOXO1 subcellular localization. Ectopic expression of PTP-MEG2 in cells inhibited insulin-induced phosphorylation of the insulin receptor, while RNAi-mediated reduction of PTP-MEG2 transcript levels enhanced insulin action. Additionally, adenoviral-mediated depletion of PTP-MEG2 in livers of diabetic (db/db) mice resulted in insulin sensitization and normalization of hyperglycemia. These data implicate PTP-MEG2 as a mediator of blood glucose homeostasis through antagonism of insulin signaling, and suggest that modulation of PTP-MEG2 activity may be an effective strategy in the treatment of type 2 diabetes

Insulin-inducible SMILE inhibits hepatic gluconeogenesis

The role of a glucagon/cAMP-dependent protein kinase–inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner–interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ−/−) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4–mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes

Applications of controllable smart fluids to mechanical systems

For this special issue, 20 papers have been received, and three of which have been withdrawn. After strict review processes by the world-wide experts on the smart fluids technology, 10 papers have been accepted and are published here.The published papers cover various application devices and systems, which can be controllable to achieve desired performances by applying the external fields to the smart fluid domains. A brief summary of each application item proposed in the published papers is given as follows

Roles of Protein Arginine Methyltransferases in the Control of Glucose Metabolism

Glucose homeostasis is tightly controlled by the regulation of glucose production in the liver and glucose uptake into peripheral tissues, such as skeletal muscle and adipose tissue. Under prolonged fasting, hepatic gluconeogenesis is mainly responsible for glucose production in the liver, which is essential for tissues, organs, and cells, such as skeletal muscle, the brain, and red blood cells. Hepatic gluconeogenesis is controlled in part by the concerted actions of transcriptional regulators. Fasting signals are relayed by various intracellular enzymes, such as kinases, phosphatases, acetyltransferases, and deacetylases, which affect the transcriptional activity of transcription factors and transcriptional coactivators for gluconeogenic genes. Protein arginine methyltransferases (PRMTs) were recently added to the list of enzymes that are critical for regulating transcription in hepatic gluconeogenesis. In this review, we briefly discuss general aspects of PRMTs in the control of transcription. More specifically, we summarize the roles of four PRMTs: PRMT1, PRMT 4, PRMT 5, and PRMT 6, in the control of hepatic gluconeogenesis through specific regulation of FoxO1- and CREB-dependent transcriptional events

Fast food diet-induced non-alcoholic fatty liver disease exerts early protective effect against acetaminophen intoxication in mice

Abstract Background Acetaminophen (APAP) is a readily available and safe painkiller. However, its overdose is the most common cause of acute liver injury (ALI). Many predisposing factors contribute to susceptibility to APAP-induced ALI. Non-alcoholic fatty liver disease (NAFLD), the major cause of chronic liver disease, is considered an important predictor of APAP-induced ALI, although the exact mechanism controversial. In this study, we aimed to elucidate the effects of NAFLD on APAP-induced ALI. Methods Two groups of mice, normal chow (NC) diet-fed and fast food (FF) diet-fed mice for 14 weeks, were further divided into two subgroups: intraperitoneally injected with either saline (NC-S and FF-S groups) or APAP (NC-A and FF-A groups). Biochemical tests, histological analysis, quantitative PCR, and western blotting were conducted. Results Alanine aminotransferase (ALT) level (199.0 ± 39.0 vs. 63.8 ± 7.4 IU/L, p < 0.05) and NAFLD activity score (0 vs. 4.5 ± 0.22) were significantly higher in mice in FF-S group than those in NC-S group. ALI features such as ALT level (8447.8 ± 1185.3 vs. 836.6 ± 185.1 IU/L, p < 0.001) and centrizonal necrosis were prominent and mRNA levels of Trib3 (RR, 1.81) was high in mice in the NC-A group. Levels of CYP2E1 and anti-inflammatory molecules such as PPAR-γ, p62, and NRF2 were high in mice in the FF-A group. Conclusions Our results showed that while the FF diet clearly induced non-alcoholic steatohepatitis and metabolic syndrome, NAFLD also attenuates APAP-induced ALI by inducing anti-inflammatory molecules such as PPAR-γ