Abstract. Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased. We previously evaluated the expression of fatty acid metabolism-related genes in NAFLD and reported changes in expression that could contribute to increased fatty acid synthesis. In the present study, we evaluated the expression of additional fatty acid metabolism-related genes in larger groups of NAFLD (n=26) and normal liver (n=10) samples. The target genes for real-time PCR analysis were as follows: acetyl-CoA carboxylase (ACC) 1, ACC2, fatty acid synthase (FAS), sterol regulatory element-binding protein 1c (SREBP-1c), and adipose differentiation-related protein (ADRP) for evaluation of de novo synthesis and uptake of fatty acids; carnitine palmitoyltransferase 1a (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), long-chain L-3-hydroxyacylcoenzyme A dehydrogenase α (HADHα), uncoupling protein 2 (UCP2), straight-chain acyl-CoA oxidase (ACOX), branched-chain acyl-CoA oxidase (BOX), cytochrome P450 2E1 (CYP2E1), CYP4A11, and peroxisome proliferatoractivated receptor (PPAR)α for oxidation in the mitochondria, peroxisomes and microsomes; superoxide dismutase (SOD), catalase, and glutathione synthetase (GSS) for antioxidant pathways; and diacylglycerol O-acyltransferase 1 (DGAT1), PPARγ, and hormone-sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, although fatty acids accumulated in hepatocytes, their de novo synthesis and uptake were up-regulated in association with increased expression of ACC1, FAS, SREBP-1c, and ADRP. Fatty acid oxidation-related genes, LCAD, HADHα, UCP2, ACOX, BOX, CYP2E1, and CYP4A11, were all overexpressed, indicating that oxidation was enhanced in NAFLD, whereas the expression of CTP1a and PPARα was decreased. Furthermore, SOD and catalase were also overexpressed, indicating that antioxidant pathways are activated to neutralize reactive oxygen species (ROS), which are overproduced during oxidative processes. The expression of DGAT1 was up-regulated without increased PPARγ expression, whereas the expression of HSL was decreased. Our data indicated the following regarding NAFLD: i) increased de novo synthesis and uptake of fatty acids lead to further fatty acid accumulation in hepatocytes; ii) mitochondrial fatty acid oxidation is decreased or fully activated; iii) in order to complement the function of mitochondria (ß-oxidation), peroxisomal (ß-oxidation) and microsomal (ω-oxidation) oxidation is up-regulated to decrease fatty acid accumulation; iv) antioxidant pathways including SOD and catalase are enhanced to neutralize ROS overproduced during mitochondrial, peroxisomal, and microsomal oxidation; and v) lipid droplet formation is enhanced due to increased DGAT expression and decreased HSL expression. Further studies will be needed to clarify how fatty acid synthesis is increased by SREBP-1c, which is under the control of insulin and AMP-activated protein kinase. IntroductionNonalcoholic fatty liver disease...

Abstract. Nonalcoholic fatty liver disease (NAFLD) is a common liver disease whose prevalence has increased markedly. We reported previously that fatty acid synthesis was enhanced in NAFLD with the accumulation of fatty acids. To clarify the disorder, we evaluated the expression of genes regulating fatty acid synthesis by real-time PCR using samples from NAFLD (n=22) and normal liver (control; n=10). A major regulator of fatty acids synthesis is sterol regulatory element-binding protein-1c (SREBP-1c). Its expression was significantly higher in NAFLD, nearly 5-fold greater than the controls. SREBP-1c is positively regulated by insulin signaling pathways, including insulin receptor substrate (IRS)-1 and -2. In NAFLD, IRS-1 expression was enhanced and correlated positively with SREBP-1c expression. In contrast, IRS-2 expression decreased by 50% and was not correlated with SREBP-1c. Forkhead box protein A2 (Foxa2) is a positive regulator of fatty acid oxidation and is itself negatively regulated by IRSs. Foxa2 expression increased in NAFLD and showed a negative correlation with IRS-2, but not with IRS-1, expression. It is known that SREBP-1c is negatively regulated by AMPactivated protein kinase (AMPK) but expression levels of AMPK in NAFLD were almost equal to those of the controls. These data indicate that, in NAFLD, insulin signaling via IRS-1 causes the up-regulation of SREBP1-c, leading to the increased synthesis of fatty acids by the hepatocytes; negative feedback regulation via AMPK does not occur and the activation of Foxa2, following a decrease of IRS-2, upregulates fatty acid oxidation. IntroductionNonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction (1-3) and its prevalence has been increasing markedly (4-6). Furthermore, nonalcoholic steatohepatitis (NASH), a severe form of NAFLD accompanied by hepatitis and fibrosis, may progress to cirrhosis and hepatic failure (7,8). NAFLD is often found in patients with obesity and/or insulin resistance, however, its precise cause remains unclear. Therefore, it is important to understand the features of lipid metabolism, particularly fatty acid metabolism, in NAFLD. Previously, we evaluated the expression levels of genes involved in fatty acid metabolism in the liver with NAFLD and found that the expression of those genes including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), was up-regulated, indicating that fatty acid synthesis was enhanced in hepatocytes, leading to the accumulation of fatty acids (9,10).Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate the expression of genes involved in lipid synthesis, and SREBP-1c positively regulates the expression of genes encoding lipogenic enzymes including ACC and FAS (11,12). Insulin is a well-known stimulator of lipogenesis and activates the hepatic expression of 14). Insulin receptor substrate (IRS) proteins, a family of docking molecules, connect insulin receptor activation to essential downstream cascad...

These findings suggest that LXR acts as one of the main regulators of lipid metabolism by regulating SREBP-1c expression in NAFLD.

In non-obese NAFLD patients: 1) although visceral fat was increased, insulin resistance and/or dysregulated secretion of adipocytokines was not necessarily shown; 2) intakes of total energy and carbohydrates were not excessive, although dietary cholesterol was superabundant and dietary PUFAs were significantly lower compared with those in obese patients; and 3) characteristic fat intake may be associated with the formation of NAFLD.

The results of this study indicate that our short-term treatment effectively reduced steatosis and contributed to safer LDLT. Our findings also suggest that even severely steatotic livers can be used for LDLT grafting subsequent to our short-term treatment regimen.

Abstract. Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic β-cells. DPP4 is also involved in the regulation of T cellmediated inflammatory processes. These properties of DPP4 suggest that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD). Hepatic DPP4 mRNA expression levels were analyzed by real-time PCR using liver biopsy samples from 17 NAFLD patients and 10 healthy subjects. In NAFLD patients, we also examined correlations between DPP4 expression levels and metabolic factors, including homeostasis model assessment-insulin resistance (HOMA-IR), body mass index (BMI), and serum cholesterol and triglyceride levels. To examine the potential effects of nutritional factors, DPP4 expression levels were analyzed in HepG2 cells subjected to various culture conditions. Hepatic DPP4 mRNA expression was significantly greater in NAFLD patients than in control subjects. DPP4 expression levels were negatively correlated with HOMA-IR and positively correlated with serum cholesterol levels. In HepG2 cells, high glucose significantly enhanced DPP4 expression, whereas insulin, fatty acids and cholesterol did not. Increased hepatic expression of DPP4 in NAFLD may be associated with metabolic factors, including insulin resistance, and may adversely affect glucose metabolism in this liver disease. IntroductionNon-alcoholic fatty liver disease (NAFLD) is a clinicopathological disorder characterized by the accumulation of triglycerides in hepatocytes. The incidence of NAFLD has increased markedly in recent years, accompanying the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) (1). More than 10% of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which is characterized by inflammatory cell infiltration and ballooning of hepatocytes in the liver. Liver cirrhosis and hepatocellular carcinoma occur in several patients with NASH (2). Obesity and insulin resistance (IR) are believed to be involved in the pathogenesis of NAFLD (3). Increased hepatic uptake of fatty acids as a result of elevated triglyceride degradation in adipose tissue causes hepatic fat accumulation. Reactive oxygen species (ROS) produced during lipid oxidation may induce hepatocyte death and inflammatory reactions. IR also reduces glucose uptake in muscles and diminishes insulin-dependent suppression of gluconeogenesis, ultimately progressing to T2DM (4).Dipeptidyl peptidase-4 (DPP4) inhibitors were recently introduced for the treatment of T2DM (5). DPP4 degrades glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from pancreatic β-cells. DPP4 inhibitors enhance glucose-dependent insulin secretion by suppressing GLP-1 degradation. However, the physiological functions of DPP4 are not fully understood. In addition to its effect on GLP-1, multiple activities of DPP4 have been reported in various cellular processes. Of note, DPP4 seems to influence inflammation by regu...

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IκB kinase (IKK) α–dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK-α activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN-α induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK-α and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN-α induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2–Rac signaling pathway acts in parallel with TLR engagement to control IKK-α activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN–related autoimmune diseases.

Background and Aims:  Magnifying endoscopy (ME) with narrow‐band imaging (NBI) revealed a white opaque substance (WOS) within the superficial part of the gastric neoplasia; however, its nature has remained obscure. A WOS noted within the duodenum was reported to comprise lipid droplets (LD) absorbed by the duodenal epithelium. We attempted to ascertain whether the WOS within gastric neoplasia could also comprise LD and whether the presence of this WOS could be correlated with a specific phenotype. Methods:  Forty‐three patients with early gastric epithelial neoplasia underwent ME with NBI. The presence or absence of WOS in the neoplasias was recorded based on the findings of ME with NBI. One biopsy specimen was taken from each of the neoplasias. Cryostat sections underwent oil red O staining for LD. Serial sections were immunostained using the first antibody of CD10, MUC2, CDX2, human gastric mucin, MUC5AC and MUC6. The tissue phenotype was classified as intestinal (I), gastric (G) and gastrointestinal (GI) type based on the results of immunostaining. In total, 49 gastric neoplasias from 43 patients were investigated. Results:  Prevalence of LD in WOS‐positive versus WOS‐negative lesions was 96.2% (25/26) and 4.3% (1/23), respectively (P < 0.001, Fisher's exact test). WOS was present in GI‐ and I‐type lesions, but not in G‐type lesions. Conclusions:  WOS may be LD that have been accumulated in the superficial part of the gastric neoplasia of a certain intestinal phenotype.