bluuebunny/crossref_metadata_2025 huggingface dataset:
One Clock-Cycle Response 0.5 m CMOS Dual-Mode DC-DC Bypass Boost Converter Stable over Wide Variations
Authors: Keskar Neeraj A. , Rincón-Mora Gabriel A.
Published: May 2010

Power supplies in portable applications must not only conform and adapt to their highly integrated on-chip and in-package environments but also, more intrinsically, respond quickly to fast load dumps to achieve and maintain high accuracy. The frequency-compensation network, however, limits speed and regulation performance because it must cater to all combinations of filter capacitor , inductor L, and 's equivalent series resistance

resulting from tolerance and modal design targets. As such, it must compensate the worst-case condition and therefore restrain the performance of all other possible scenarios, even if the likelihood of occurrence of the latter is considerably high and the former substantially low. Sigma-delta () control, which addresses this issue in buck converters by easing its compensation requirements and offering one-cycle transient response, has not been able to simultaneously achieve high bandwidth, high accuracy, and wide compliance in boost converters. This paper presents a dual-mode boost bypass converter, which by using a high-bandwidth bypass path only during transient load-dump events was experimentally 1.41 to 6 times faster than the state of the art in current-mode boost supplies, and this without any compromise in compliance range (0–50 m, 1–30 H, and 1–350 F).
A Winner′s Mean Earnings in Lottery and Inverse Moments of the Binomial Distribution
Authors: Drakakis Konstantinos
Published: May 2010

We study the mean earnings of a lottery winner as a function of the numbernof participants in the lottery and of the success probabilityp. We show, in particular, that, for fixedp, there exists an optimal value ofnwhere the mean earnings are maximized. We also establish a relation with the inverse moments of a binomial distribution and suggest new formulas (exact and approximate) for them.
Some Variational Results Using Generalizations of Sequential Lower Semicontinuity
Authors: Bottaro Aruffo Ada , Bottaro Gianfranco
Published: May 2010

Kirk and Saliga and then Chen et al. introduced lower semicontinuity from above, a generalization of sequential lower semicontinuity, and they showed that well-known results, such as Ekeland's variational principle and Caristi's fixed point theorem, remain still true under lower semicontinuity from above. In a previous paper we introduced a new concept that generalizes lower semicontinuity from above. In the present one we continue such study, also introducing other two new generalizations of lower semicontinuity from above; we study such extensions, compare each other five concepts (sequential lower semicontinuity, lower semicontinuity from above, the one by us previously introduced, and the two here defined) and, in particular, we show that the above quoted well-known results remain still true under one of our such generalizations.
Development of a Simple Closed-Loop Type Algorithm for Determination of Variable Blank Holder Force Trajectory and Its Applications to Square Cup Deep Drawing
Authors: Kitayama Satoshi , Hamano Satoshi , Yamazaki Koetsu
Published: May 2010

In deep drawing, a low blank holder force (BHF) can cause wrinkling, while a high BHF can lead to tearing. In this study, a variable blank holder force (VBHF) approach to deep drawing is employed, and a simple closed-loop type algorithm is developed for the VBHF trajectory. The proposed algorithm is divided into two phases. The objective of the first phase is to check wrinkling and tearing. In this phase, a low BHF is used as the initial BHF, which is then increased to prevent wrinkling while controlling tearing. This phase of the algorithm is terminated when tearing occurs. In numerical simulation, the distance between the die and the blank holder is used to measure wrinkling, and the minimum thickness of the blank is used to determine the tearing. In the second phase of the algorithm, the deviations in thickness of the part are iteratively examined, without neglecting the occurrence of wrinkling. One of the advantages of using VBHF instead of constant BHF is that it reduces the forming energy. The validity of the proposed algorithm is examined comparing numerical simulation and experimental results. Finally, the proposed algorithm is also applied to obtain the segmented VBHF trajectory.
Natural Killer T Cells within the Liver: Conductors of the Hepatic Immune Orchestra
Authors: Swain Mark G.
Published: May 2010

Natural killer T (NKT) cells are distinct innate immune T cells which play a key role in the pathogenesis of various immune-mediated liver diseases. NKT cells are traditionally defined as cells that co-express the T cell receptor (TCR) and certain natural killer cell surface markers (e.g. NK1.1 in some mouse strains). Based on CD1d restriction, they are broadly classified as invariant (iNKT) and noninvariant NKT cells. Both NKT cell types are abundant within the liver and, mainly through the study of animal models of immune-mediated liver injury, the role of NKT cells in the context of liver inflammation is becoming better understood. iNKT cells are the NKT cell subtype which has been most well characterized, and therefore this paper will focus mainly on iNKT cells. NKT cells recognize both host and microbial glycolipid antigens, presented by antigen-presenting cells in the context of the MHC class I- like molecule CD1d, via their T cell receptor. Upon activation, NKT cells rapidly release large quantities of T helper type 1 (Th1; e.g. IFN-γ, TNF-α), Th2 (e.g. IL-4, IL-10), and Th17 (e.g. IL-17, IL-22) type cytokines, with diverse immunoregulatory and immunomodulatory effects. Moreover, through the release of these cytokines, NKT cells can drive subsequent downstream immune responses in tissues such as the liver, including the upregulation of adhesion molecule expression and increased chemokine production. By regulating immune cell adhesion pathways and chemokine secretion, NKT cells can direct both pro-inflammatory (e.g. Th1 cell) and anti-inflammatory (e.g. regulatory T cell) cell infiltration into the liver. Through this mechanism, NKT cells orchestrate a balance between pro- and anti-inflammatory responses within the liver during immune-mediated liver damage. This paper highlights the diverse roles played by iNKT cells as master regulators of immune-mediated liver injury.
Mechanisms of T Cell Death in the Liver: To Bim or Not to Bim?
Authors: Holz Lauren E. , Bowen David G. , Bertolino Patrick
Published: May 2010

Despite being a non-lymphoid organ, the liver displays immunological properties distinct from other solid organs and is associated with the induction of T cell tolerance. This property has been demonstrated in several clinical settings including transplantation and hepatotropic viral infections, such as those induced by hepatitis B and C viruses. Many models have been proposed to explain the ‘liver tolerance effect’, but the molecular and cellular mechanism(s) mediating this phenomenon remain unknown. Using transgenic mouse models, we have previously shown that the liver is the only non-lymphoid organ able to retain and activate naïve CD8+ T cells independently of lymphoid tissues in an antigen-specific manner. These findings, confirmed by other groups, have opened new possibilities to explain the remarkable capacity of the liver to induce antigen-specific tolerance in transplantation and following infection by hepatotropic viruses, such as the hepatitis C and B viruses. In our models, T cells activated by hepatocytes that proliferate die by neglect in a Bim-dependent manner. This paper will thus review the evidence showing Bim playing a critical role following intrahepatic primary T cell activation.
Host Mechanisms in Viral Hepatitis
Authors: Lang Karl S.
Published: May 2010

Hepatitis, a common human disease, may be followed by severe liver injury, eventually leading to fatty liver, liver fibrosis and hepatocellular carcinoma. CD8 T cells are a double-edged sword in the response to infection with the hepatitis virus. On one hand, rapid activation of CD8 T cells is critically important for the elimination of the virus. On the other hand, in persistent viral infection, the activation of CD8 T cells substantially contributes to liver injury. The clinical course of hepatitis, thus, critically depends on mechanisms regulating the activity of CD8 T cells. In observations in human hepatitis and in mice infected with the lymphocytic choriomeningitis virus, the clinical course of hepatitis is modified by several immunological factors including neutralizing antibodies: RIG-I, TLRs, MyD88, interferon type I, TNF-α, MHC I, Tap, TCR, CD8, IL-2, IL-7, PD-1, IFN-I, IL-10, IFN-γ, perforins, serotonin and iNOS (table 1) . Additional experimental effort is needed to understand the concerted interplay of those molecules in viral hepatitis of man and mice.
The Role of Chemokines in the Recruitment of Lymphocytes to the Liver
Authors: Oo Ye H. , Shetty Shishir , Adams David H.
Published: May 2010

Chemokines direct leukocyte trafficking and positioning within tissues, thus playing critical roles in regulating immune responses and inflammation. The chemokine system is complex, involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low-flow environment through which leukocytes are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum, fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure; at the other end, diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is characterized by a T lymphocyte-rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells, and more recently Th17 and Th9 cells, which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate disease pathogenesis and open up new therapeutic approaches to modulate recruitment in favor of resolution rather than injury.
Developments in Cancer Immunotherapy
Authors: van den Broek Maries , von Boehmer Lotta , Knuth Alexander
Published: May 2010

Significant advances have been made in the field of cancer immunology and immunotherapy over the last three decades. An important step forward was the identification of human cancer antigens eliciting spontaneous immune responses in cancer patients. The most immunogenic human cancer antigens known to date belong to the cancer-testis family of antigens, which are proteins expressed in various types of cancer but not in any healthy tissues except germ cells. The aim of cancer immunotherapy is to induce or boost the existing tumor-specific immune response by vaccinating with a relevant antigen together with an adjuvant. Immunization together with an adjuvant will induce a strong and effective immune response or can qualitatively and quantitatively improve existing responses. As selective outgrowth of antigen-loss variants due to immunoediting in vivo may occur during vaccination of cancer patients, singular metastatic failure sites of disease should be surgically removed and tested for antigen expression as antigen-negative (or loss) variants may have survived the pressure of the immune system. At this rather early stage of development, cancer immunotherapy should be offered to cancer patients only within carefully monitored clinical trials of experienced clinical research teams. In addition, it may be rewarding to include patients with early-stage disease in immunotherapy trials, as immunoediting of the tumor and immune escape may be less pronounced.
Adaptive Immunity in Autoimmune Hepatitis
Authors: Longhi Maria Serena , Ma Yun , Mieli-Vergani Giorgina , Vergani Diego
Published: May 2010

The histological lesion of interface hepatitis, with its dense portal cell infiltrate consisting of lymphocytes, monocytes/macrophages and plasma cells, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of autoimmune hepatitis (AIH). Immunohistochemical studies, focused on the phenotype of inflammatory cells infiltrating the liver parenchyma, have shown a predominance of αβ-T cells. Amongst these cells, the majority have been CD4 helper/inducers, while a sizeable minority have consisted of CD8 cytotoxic/suppressors. Lymphocytes on non-T cell lineage included natural killer cells, monocytes/macrophages and B lymphocytes. For autoimmunity to arise, the self-antigenic peptide, embraced by an human leukocyte antigen (HLA) class II molecule, must be presented to an uncommitted T helper (TH0) lymphocyte by professional antigen-presenting cells. Once activated and according to the presence in the milieu of interleukin 12 (IL-12) or IL-4, TH0 lymphocytes can differentiate into TH1 cells, which are pivotal to macrophage activation; enhance HLA class I expression, rendering liver cells vulnerable to CD8 T-cell attack; and induce HLA class II expression on hepatocytes; or they can differentiate into TH2 cells, which produce IL-4, IL-10 and IL-13, cytokines favouring autoantibody production by B lymphocytes. Autoantigen recognition is tightly controlled by regulatory mechanisms, such as those exerted by CD4+CD25high regulatory T cells. Numerical and functional regulatory T cell impairment characterises AIH and permits the perpetuation of effector immune responses with ensuing persistent liver destruction. Advances in the study of autoreactive T cells stem mostly from AIH type 2, where the main autoantigen, cytochrome P450IID6 (CYP2D6), is known to enable characterisation of antigen-specific immune responses.
Cytochrome P450 2D6 as a Model Antigen
Authors: Christen Urs , Holdener Martin , Hintermann Edith
Published: May 2010

Cytochrome P450 2D6 (CYP2D6) has been identified as the major autoantigen in type 2 autoimmune hepatitis (AIH). However, because of a lack of appropriate animal models, the etiology of AIH is still poorly understood. We generated a mouse model for AIH using the human CYP2D6 as a triggering molecule for autoimmunity. We infected wild-type FVB mice with an adenovirus expressing human CYP2D6 (Ad-2D6) to break self-tolerance to the mouse CYP2D6 homologues. Ad-2D6-infected mice showed persistent features of liver damage including hepatic fibrosis, cellular infiltrations, focal-to-confluent necrosis and generation of anti-CYP2D6 antibodies, which predominantly recognized the identical immunodominant epitope recognized by LKM-1 antibodies from AIH patients. Interestingly, Ad-2D6 infection of transgenic mice expressing the human CYP2D6 (CYP2D6 mice) resulted in delayed kinetics and reduced severity of liver damage. However, the quantity and quality of anti-CYP2D6 antibodies was only moderately reduced in CYP2D6 mice. In contrast, the frequency of CYP2D6-specific CD4 and CD8 T cells was dramatically decreased in CYP2D6 mice, indicating the presence of a strong T cell tolerance to human CYP2D6 established in CYP2D6 mice, but not in wild-type mice. CYP2D6-specific T cells reacted to human CYP2D6 peptides with intermediate homology to the mouse homologues, but not to those with high homology, indicating that molecular mimicry rather than molecular identity breaks tolerance and subsequently causes severe persistent autoimmune liver damage. The CYP2D6 model provides a platform to investigate mechanisms involved in the immunopathogenesis of autoimmune-mediated chronic hepatic injury and evaluate possible ways of therapeutic interference.
Therapeutic Options to Treat Autoimmune Hepatitis in 2009
Authors: Strassburg Christian P.
Published: May 2010

First described in 1950, autoimmune hepatitis (AIH) was the first chronic liver disease with a favorable response to drug therapy and a dismal prognosis when left untreated. In the decades since the first treatment studies, the basic strategy of inducing remission with steroids and azathioprine have not been modified in principle. The main problems are a timely diagnosis before cirrhosis develops, the avoidance of immunosuppressant side effects, nonresponders to standard induction therapy and adherence to therapy. Alternative drugs for immunosuppression have been tested in small series and include transplant immunosuppressants. A large multicenter prospective treatment trial suggests that budesonide may offer an alternative in noncirrhotic AIH patients, capable of minimizing unwanted steroid effects. The ultimate treatment approach is liver transplantation. Although only 4% of transplant patients are transplanted with the diagnosis AIH, the risk for graft loss because of recurrence has to be considered and recurrent AIH treated after transplantation.
New Insights into Autoimmune Cholangitis through Animal Models
Authors: Trauner Michael , Fickert Peter , Baghdasaryan Anna , Claudel Thierry , Halilbasic Emina , Moustafa Tarek , Wagner Martin , Zollner Gernot
Published: May 2010

Improving our understanding of the pathogenesis of chronic immune-mediated cholangiopathies such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), as well as the development of novel diagnostic, prognostic and therapeutic tools for these disorders critically depends on easily reproducible animal models. Recently, several spontaneous mouse models for PBC (not requiring previous manipulations for breakdown of immunotolerance) have been reported, including NOD.c3c4 and NOD.c3c4-derived mice, IL-2Rα–/– mice, dominant negative TGF-β receptor II mice and Ae2a,b–/– mice. To date, no animal model exhibits all of the attributes of PSC. Rodent models induced by bacterial cell components or colitis may help to explain the strong association between PSC and inflammatory bowel disease. Other models include direct injury to biliary epithelia, peribiliary vascular endothelia or portal venous endothelia. Mice with targeted disruption of the Mdr2 (Abcb4) gene encoding a canalicular phospholipid flippase (Mdr2–/– mice) spontaneously develop sclerosing cholangitis with macroscopic and microscopic features of human PSC. Another example for a transporter involved in the pathogenesis of sclerosing cholangitis is the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7). Xenobiotics and drugs may also lead to bile duct injury and biliary fibrosis via direct toxic and indirect immune-mediated injury. Hydrophobic bile acids, such as lithocholic acid, cause bile duct injury and destructive cholangitis with periductal fibrosis resembling sclerosing cholangitis. These models have enhanced our understanding of the pathogenesis of PBC and PSC and will hopefully result in improved treatment of these disorders.
The Etiology Mystery in Primary Biliary Cirrhosis
Authors: Selmi Carlo , Gershwin M. Eric
Published: May 2010

The etiology of primary biliary cirrhosis remains largely unknown despite numerous lines of evidence that have been recently proposed or supported. Primary biliary cirrhosis is a chronic cholestatic liver disease for which an autoimmune pathogenesis is widely accepted, mostly based on the presence of autoantibodies and autoreactive T cells. Cumulatively, association and twin studies suggest that both a susceptible genetic background and environmental factors determine disease onset. Multiple infectious and chemical candidates may contribute to the disease onset in a genetically susceptible host. Several murine models have been recently reported and include genetically determined ones as well as models induced by immunization with chemicals and bacteria.
Hepatitis Delta: Immunopathogenesis and Clinical Challenges
Authors: Grabowski Jan , Wedemeyer Heiner
Published: May 2010

Hepatitis delta is caused by infection with the hepatitis D virus (HDV) and is considered to be the most severe form of viral hepatitis in humans. Hepatitis delta occurs only in hepatitis B virus (HBV) surface antigen (HBsAg)-positive individuals as HDV is a defective RNA virus which requires the HBsAg for complete replication and transmission. Eight different HDV genotypes have been described with specific geographic distributions and distinct clinical courses. HDV/HBV co-infection can be associated with complex and dynamic viral dominance patterns. While HDV is frequently the dominating virus not only in HBV/HDV co-infection, but also in HBV/HCV/HDV triple-infected patients, the fluctuating courses of HDV and HBV viremia can be observed in other patients. Chronic HDV infection leads to more severe liver disease than HBV monoinfection with accelerated fibrosis progression, earlier hepatic decompensation and an increased risk for the development of hepatocellular carcinoma. However and in contrast to HCV infection, hepatic decompensation, rather than development of liver cancer, is the first clinical endpoint that develops during the course of infection. So far, only interferon-α treatment has proven antiviral activity against HDV in humans and has been linked to improved long-term outcome. Recent studies on the use of pegylated interferon showed a sustained virological response concerning HDV-RNA in about one quarter of the patients. HDV-specific immune responses might be associated with the response to treatment. Novel alternative treatment options, including prenylation inhibitors, are still awaiting clinical development for delta hepatitis. So far, only few studies have investigated immune responses against HDV and HBV in humans.
Immune Responses in Hepatocellular Carcinoma
Authors: Korangy Firouzeh , Höchst Bastian , Manns Michael P. , Greten Tim F.
Published: May 2010

Hepatocellular carcinoma (HCC) represents the third most common cause of cancer-related deaths worldwide and efficient treatment options are urgently needed. Based on its pathogenesis as well as a number of correlative studies, immunotherapy represents a potential therapeutic option for patients with HCC. However, tumors have also evolved numerous immune escape mechanisms, such as the generation of cells with immune suppressor functions, including regulatory T cells and myeloid-derived suppressor cells. It has been shown that these suppressor cells mask tumor-specific immune responses in patients with HCC. We propose that targeting suppressor cells either alone or in combination with conventional immunotherapy should be further evaluated in HCC patients.
Epidemiology of Non-Alcoholic Fatty Liver Disease
Authors: Bellentani Stefano , Scaglioni Federica , Marino Mariano , Bedogni Giorgio
Published: May 2010

Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. The prevalence of NAFLD in the general population of Western countries is 20–30%. About 2–3% of the general population is estimated to have non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocarcinoma. As a rule, the prevalence of NAFLD is higher in males and increases with increasing age, and it is influenced by the diagnostic method and the characteristics of the population, especially lifestyle habits. Population-based studies provide better estimates of the prevalence of NAFLD as compared to autoptic and clinical studies, but few such studies have been performed to date. The diagnosis of NAFLD in population studies is usually obtained by ultrasonography, which is known to underestimate the prevalence of fatty liver. The Dallas Heart Study and the Dionysos Study reported that 30% of the adults in the USA and 25% in Italy have NAFLD. In these studies, 79% and 55% of patients with NAFLD had normal aminotransferase levels, showing that liver enzymes are not surrogate markers of NAFLD in the general population. Noninvasive markers such as the fatty liver index obtained from the Dionysos Study may be useful to screen for NAFLD in the general population. The most important risk factors for NAFLD are male gender, age, obesity, insulin resistance and the cardiometabolic alterations that define the metabolic syndrome. The prevalence of NAFLD is 80–90% in obese adults, 30–50% in patients with diabetes and up to 90% in patients with hyperlipidemia. The prevalence of NAFLD among children is 3–10%, rising up to 40–70% among obese children. Moreover, pediatric NAFLD increased from about 3% a decade ago to 5% today, with a male-to-female ratio of 2:1. The incidence and natural history of NAFLD are still not well defined, but it is recognized that the majority of individuals with NAFLD do not develop NASH. The incidence of NAFLD is probably increasing in Western countries, strictly linked to lifestyle habits.
The Role of Cytokines in Non-Alcoholic Fatty Liver Disease
Authors: Tilg Herbert
Published: May 2010

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity and diabetes, and is characterized by insulin resistance (IR). Cytokines and adipocytokines (i.e. mediators mainly derived from adipose tissue) play a major role in the orchestration of inflammatory processes throughout the body. In addition, many of these mediators are able to regulate very diverse functions including inflammatory, immune and metabolic processes such as IR. The pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are critically involved in the pathophysiology of various aspects of human NAFLD. The importance of TNF-α in human and animal fatty liver diseases, both due to genetic manipulation and overnutrition, has been demonstrated. Furthermore, neutralization of TNF-α activity improves IR and fatty liver disease in animals. IL-6 is derived from many cells throughout the body including adipocytes. Serum levels of this cytokine correlate remarkably well with the presence of IR, and adipose tissue-derived IL-6 has been shown to regulate hepatic IR via upregulation of SOCS3. Adiponectin is a potent TNF-α-neutralizing and anti-inflammatory adipocytokine, and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are mediated via suppression of TNF-α synthesis as well as induction of anti-inflammatory cytokines such as IL-10 or IL-1 receptor antagonist. Therefore, the balance between pro- and anti-inflammatory acting cytokines/adipocytokines appears to play a key role in hepatic and systemic insulin action, and they are supposed to have important functions in the development of NAFLD.
Chemokines as Immune Mediators of Liver Diseases Related to the Metabolic Syndrome
Authors: Berres Marie-Luise , Nellen Andreas , Wasmuth Hermann E.
Published: May 2010

Background/Aims: Chemokines are small chemotactic molecules which regulate the infiltration of immune cells to sites of inflammatory injury. In recent years their contribution to the initiation and perpetuation of liver injury has been better defined. However, the role of chemokines in liver diseases related to the metabolic syndrome still needs to be elucidated in detail. Methods: Chemokines were mostly detected at the mRNA level in the liver and as proteins in the serum of patients with non-alcoholic steatohepatitis (NASH) or fatty liver. Animals with targeted deletion of chemokines have recently been subjected to NASH models to functionally dissect the role of chemokines in fatty liver diseases. Results: In human liver with features of NASH, different CC and CXC chemokines have been detected at elevated mRNA levels in comparison to healthy subjects. Some of these chemokines have also been associated with NASH by demonstrating higher serum levels in affected patients. Until now, only a few animal models have been analyzed with respect to the functional role of these molecules. However, data from CCL2 and CXCR3 knockout mice suggest that these pathways are important in liver injury. CCL2 seems to influence the infiltration of macrophages to adipose tissue and thereby modulate insulin resistance. Conclusions: The further elucidation of the pathophysiology of NASH will lead to new therapeutic options to halt or reverse progressive liver disease. In this respect, chemokines are attractive target molecules, as they influence immunologic and metabolic pathways and the first oral chemokine receptor antagonists have already been licensed for humans.
Liver Fat in the Pathogenesis of Insulin Resistance and Type 2 Diabetes
Authors: Yki-Järvinen Hannele
Published: May 2010

The pathogenesis of type 2 diabetes involves both insulin resistance and defects in insulin secretion. Although obesity and physical inactivity have precipitated the epidemic of type 2 diabetes, the metabolic abnormalities associated with a sedentary lifestyle are better predictors of type 2 diabetes and cardiovascular disease than obesity alone. Some of these metabolic abnormalities, which are either causes or consequences of insulin resistance, have been called the metabolic syndrome. Fat accumulation in the liver due to non-alcoholic causes (non-alcoholic fatty liver disease) has also been shown to be an obesity-independent predictor of type 2 diabetes in multiple prospective studies. Since the liver is a key site of action of insulin, it seems reasonable to postulate that subjects who deposit excessive amounts of fat in the liver are those who also are at risk of developing the metabolic syndrome. Mechanistic studies support this hypothesis. Once fatty, the liver is resistant to the actions of insulin to inhibit both production of glucose and very-low-density lipoprotein, which results in mild hyperglycemia, compensatory hyperinsulinemia and hypertriglyceridemia. The latter leads to lowering of high-density lipoprotein cholesterol and formation of atherogenic small dense low-density lipoprotein particles. These data suggest that the metabolic syndrome and non-alcoholic fatty liver disease are essentially two definitions of the same problem. In subjects who cannot sustain hyperinsulinemia to maintain glucose concentrations in the nondiabetic range, overt hyperglycemia, i.e. type 2 diabetes, develops.
The Role of Non-Alcoholic Fatty Liver Disease in Cardiovascular Disease
Authors: Perseghin Gianluca
Published: May 2010

Background/Aims: Fatty liver is the hepatic component of the metabolic syndrome. Insulin resistance, the pathogenic driver of the metabolic syndrome, refers to a constellation of features such as overweight/obesity, glucose intolerance, dyslipidemia and hypertension, all of which are important risk factors for cardiovascular disease (CVD). The aim of this article is to summarize the available data linking non-alcoholic fatty liver disease (NAFLD) with CVD. Methods: Two approaches were used to address this issue. First, data in support of the presence of the typical in vivo pathogenic features of atherosclerosis in individuals with NAFLD were described to confirm whether or not the association between NAFLD and CVD is plausible. Second, epidemiological data linking NAFLD with CVD outcome was reviewed. Results: Individuals with NAFLD are characterized by abnormal endothelial function. Data about the carotid intima-media thickness, which as a surrogate marker of atherosclerosis, are controversial, as is higher CAD even if altered myocardial perfusion has been described. Data in support of altered cardiac intermediary metabolism and energy metabolism are more robust. Low-grade inflammation is typically linked to NAFLD and animal studies, suggested that NAFLD may represent a potential mediator of the systemic inflammation. Epidemiologic studies support a causal link between fatty liver and type 2 diabetes but the causal association between NAFLD and CVD is rather weak. Conclusion: NAFLD is characterized by the early onset of the typical metabolic and vascular pathogenic alterations of atherosclerosis. In spite of this background, the evidence for the association between NAFLD and CVD is weak.
Bile Acids as Regulators of Hepatic Lipid and Glucose Metabolism
Authors: Trauner Michael , Claudel Thierry , Fickert Peter , Moustafa Tarek , Wagner Martin
Published: May 2010

Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, bile acids (BA) also act as metabolically active signaling molecules. The flux of reabsorbed BA undergoing enterohepatic circulation, arriving in the liver with the co-absorbed nutrients (e.g. glucose, lipids), provides a signal that coordinates hepatic triglyceride (TG), glucose and energy homeostasis. As signaling molecules with systemic endocrine functions, BA can activate protein kinases A and C as well as mitogen-activated protein kinase pathways. Additionally, they are ligands for a G-protein-coupled BA receptor (TGR5/Gpbar-1) and activate nuclear receptors such as farnesoid X receptor (FXR; NR1H4). FXR and its downstream targets play a key role in the control of hepatic de novo lipogenesis, very-low-density lipoprotein-TG export and plasma TG turnover. BA-activated FXR and signal transduction pathways are also involved in the regulation of hepatic gluconeogenesis, glycogen synthesis and insulin sensitivity. Via TGR5, BA are able to stimulate glucagon-like peptide-1 secretion in the small intestine and energy expenditure in brown adipose tissue and skeletal muscle. Dysregulation of BA transport and impaired BA receptor signaling may contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Thus, BA transport and BA-controlled nuclear receptors and signaling pathways are promising drug targets for treatment of NAFLD. As such, FXR and/or TGR5 ligands have shown promising results in animal models of NAFLD and clinical pilot studies. Despite being a poor FXR and TGR5 ligand, ursodeoxycholic acid (UDCA) improves hepatic ER stress and insulin sensitivity. Notably, norUDCA, a side chain-shortened homologue of UDCA, improves fatty liver and atherosclerosis in Western diet-fed ApoE–/– mice. Collectively, these findings suggest that BA and targeting their receptor/signaling pathways may represent a promising approach to treat NAFLD and closely linked disorders such as obesity, diabetes, dyslipidemia and arteriosclerosis.
Animal Models of Non-Alcoholic Steatohepatitis: Of Mice and Man
Authors: Schattenberg J.M. , Galle P.R.
Published: May 2010

The epidemic occurrence of obesity has led to a rapid increase in the incidence of non-alcoholic fatty liver disease (NAFLD) in industrial countries. The disease spectrum includes hepatic steatosis, lobular inflammation with steatohepatitis (NASH) and varying degrees of liver fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma can develop in patients with NASH, even in the absence of cirrhosis. The majority of patients with primary NASH exhibit risk factors that define the metabolic syndrome including insulin resistance and visceral obesity. However, only a minority of patients with NAFLD progress to end-stage liver disease and, so far, predictors to identify these patients are not available. The course of disease progression appears to be slow and develops progressively over years, modulated by genetic susceptibility, nutritional misbehavior and environmental factors. Although risk factors have been identified in epidemiological studies, little is known about disease initiation and progression. This review summarizes the existing animal models of NAFLD, focusing on genetic and dietary models, and discusses their applicability in studying signaling events involved in steatohepatitis. Despite the shortcomings inherent to all experimental models, research in this field has helped to identify potential therapeutic targets and, thus, contributed significantly to our understanding of this disease. The validation and search for new in vivo and in vitro models will propagate the understanding of NASH and help clinicians to develop new treatment modalities.
Genetic and Environmental Susceptibility to Non-Alcoholic Fatty Liver Disease
Authors: Day Christopher Paul
Published: May 2010

While the majority of those with non-alcoholic fatty liver disease (NAFLD) will have simple hepatic steatosis, a minority will develop progressive steatohepatitis. Family studies and inter-ethnic variations in susceptibility suggest that genetic factors may be important in determining disease risk. Although no genetic associations with advanced NAFLD have been replicated in large studies, preliminary data suggest that polymorphisms in genes controlling lipid metabolism, pro-inflammatory cytokines, fibrotic mediators and oxidative stress may be associated with steatohepatitis and/or fibrosis. Recent whole genome-wide scans have identified genes contributing to inherited susceptibility to steatosis and it seems likely that similar approaches will identify genes associated with disease progression in the near future.
Endocannabinoids and Their Role in Fatty Liver Disease
Authors: Mallat A. , Lotersztajn S.
Published: May 2010

The endocannabinoid system comprises receptors, CB1 and CB2, their endogenous lipidic ligands and machinery dedicated to endocannabinoid synthesis and degradation. An overactive endocannabinoid system appears to contribute to the pathogenesis of several diseases, including liver diseases. With the increasing incidence of non-alcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic, the development of effective therapies is gaining considerable interest. Several recent experimental lines of evidence identify CB receptors as potential novel therapeutic targets in the management of NAFLD. Endogenous activation of peripheral CB1 receptors is a key mediator of insulin resistance and enhances liver lipogenesis in experimental models of NAFLD. Moreover, we have shown that adipose tissue CB2 receptors are markedly upregulated and promote fat inflammation, thereby contributing to insulin resistance and liver steatosis. Data from our group also indicate that tonic activation of CB1 receptors is responsible for progression of liver fibrosis, whereas CB2 receptors display anti-fibrogenic properties. The clinical relevance of these findings is supported by studies in patients with chronic hepatitis C indicating that daily cannabis use is an independent predictor of both fibrosis and steatosis severity. Moreover, preliminary data derived from clinical trials strongly suggest that selective CB1 antagonism improves insulin resistance and reduces liver fat. Tempering these promises, the first generation of CB1 antagonists raised concern due to an alarming rate of mood disorders and the development program of these molecules was suspended. Current research efforts are therefore focused on developing formulations of CB1 antagonists that do not enter the central nervous system, and preliminary experimental data obtained with such molecules are encouraging.
The Effect of Lifestyle Changes in Non-Alcoholic Fatty Liver Disease
Authors: Centis Elena , Marzocchi Rebecca , Di Domizio Silvia , Ciaravella Maria Francesca , Marchesini Giulio
Published: May 2010

Non-alcoholic fatty liver disease (NAFLD) is a clinical/biochemical condition associated with the metabolic syndrome. As the disease stems from excess calorie intake and lack of physical activity, the correction of unhealthy lifestyles is the background of any prevention and treatment strategy; drugs should remain a second-line treatment. Several studies have shown that weight loss and physical activity, the cornerstones of a healthy lifestyle, have a specific therapeutic role in NAFLD, preventing disease progression and reducing the burden of disease. Prescriptive diets have a limited long-term efficacy; after a short period, most patients resume their old habits and weight regain is the rule. Physical activity, usually in combination with diet, but also independent of weight loss, improves liver enzymes and reduces liver fat, with uncertain results on hepatic necroinflammation; however, making patients increase their physical activity is very difficult. Only a behavioral approach may give patients the practical instruments to achieve their eating and exercise goals, incorporate them into lifestyle, and maintain the results for a long period, thereby possibly guaranteeing long-term durability of change. Cognitive-behavior treatment should be provided to patients at risk of advanced liver disease, and this action should be coupled with prevention strategies at the population level. Only a synergistic approach and a global societal response might be effective in reducing the burden of advanced liver disease and premature death due to NAFLD/NASH (non-alcoholic steatohepatitis).
Surgical Treatment of Non-Alcoholic Steatohepatitis and Non-Alcoholic Fatty Liver Disease
Authors: Weiner R.A.
Published: May 2010

Background: Overweight and obesity are the most significant risk factors for the development of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) in children and adults. Both have been increasingly implicated in the genesis of hepatic fibrosis and cirrhosis. However, no consensus exists about whether weight reduction may reverse this process. Methods: To assess the effect of obesity surgery on the histological evolution of NASH, diagnosed in 284 morbidly obese patients by routine liver biopsy (‘first’ biopsy) performed during bariatric surgery, we performed a ‘second’ biopsy after 18.6 ± 8.3 months in 116 patients (109 female, 7 male). 68 patients underwent Roux-en-Y gastric bypass, 38 adjustable gastric banding and 16 biliopancreatic diversion with duodenal switch (BPD-DS). The second biopsy was taken during CHE (102) and relaparoscopy for suspected complications and revisional surgeries (12). All primary and secondary surgical procedures were done laparoscopically without intraoperative or postoperative major complications. All comorbidities were recorded pre- und postoperatively. Results: From the first to the second biopsy, BMI decreased from 55.2 ± 8.3 to 30.5 ± 6.6 kg/m2, arterial hypertension decreased from 65 to 43%, and type 2 diabetes decreased from 42 to 2%. On the first biopsy, non-alcoholic fatty liver disease (NAFLD) type 3 was observed in 186 patients (65.5%) and type 4 in 82 (28.9%). The second biopsy revealed complete regression of NAFLD in 89 patients (82.8%) and only 16 (13.8%) still had NAFLD type 1 (mild steatosis without inflammation). These two patients with NAFLD type 3 had adjustable gastric banding with insufficient weight loss (EWL <50%) in history. Complete regression of necroinflammatory activity was observed in 108 patients (93.1%). Among the 12 patients presenting fibrosis in the first biopsy, complete remission was observed in 10 and improvement in 2. Two patients with ascites during BPD-DS showed complete remission within 9–15 months. Two continued to show the same degree of fibrosis without evidence of disease activity. No worsening of steatosis, necroinflammatory activity or fibrosis was observed in any of the patients, and none progressed to cirrhosis. Conclusion: Obesity surgery improves steatosis, necroinflammatory activity and hepatic fibrosis in patients with morbid obesity and NASH. The improvement of all obesity-related comorbidities can be confirmed.
Hepatitis C Virus, Diabetes and Steatosis: Clinical Evidence in Favor of a Linkage and Role of Genotypes
Authors: Mihm Sabine
Published: May 2010

Infection with hepatitis C virus (HCV) primarily causes chronic liver disease with characteristic histopathologic features, including hepatic steatosis. Moreover, chronic hepatitis C is also closely related to insulin resistance (IR) and an increased risk of type 2 diabetes mellitus (DM). This review summarizes the available clinical evidence for a linkage of chronic HCV infection and developing IR or DM that comprises (i) retro- and prospective clinical studies, (ii) the excess risk of chronic hepatitis C patients to develop DM compared to hepatitis B patients, (iii) a preferential relationship of IR with HCV type-1, -2 or -4 infections, (iv) a correlation between IR, viral load and responsiveness to antiviral treatment and (v) a decreased incidence of DM in chronic hepatitis C after sustained virological response. This review further refers to the clinical evidence of a preferential relationship between hepatic steatosis and HCV type-3 infection, and that two distinct genotype-specific pathogenic mechanisms underlie steatosis in hepatitis C. In HCV type-3 infections, steatosis is related to viral load but not to metabolic factors, and, thus, is termed ‘viral steatosis’. In HCV type-1, -2 or -4 infections, steatosis appears to be secondary to IR and regarded as ‘metabolic steatosis’. In conclusion, multiple lines of clinical evidence support a linkage of HCV infection and both hepatic carbohydrate and lipid metabolism. The extent to which targeting the host’s metabolism by drugs or by lifestyle change translates into an improvement of health or in a better response to interferon-α will provide further valuable insights into virus-host interactions, and is topic which is currently addressed in clinical studies.
Hepatitis C Virus-Induced Steatosis: An Overview
Authors: Negro Francesco
Published: May 2010

The pathogenesis of liver damage associated with the chronic hepatitis C virus (HCV) infection is largely immunomediated. However, some frequent histopathological features, such as fatty liver, suggest a direct cytopathic effect of HCV. The direct responsibility of HCV in the pathogenesis of steatosis is shown by: (1) the association with HCV genotype 3 infection, suggesting that some viral sequences are involved in the intracellular accumulation of triglycerides; (2) the correlation between the severity of steatosis and HCV replication levels; and (3) the association between the response to antivirals and the disappearance of steatosis. Experimental studies have shown that the core protein of HCV is capable and sufficient to induce a triglyceride accumulation in hepatocytes. Moreover, the observation that chronic hepatitis C patients have reduced serum levels of apolipoprotein B suggests an interference with the very-low-density lipoprotein assembly. In patients with a sustained virological response induced by antiviral therapy, such levels are normalized. Other observations suggest that HCV may increase neolipogenesis and inhibit fatty acid degradation in mitochondria. Put together, all of these mechanisms contribute to the pathogenesis of fatty liver frequently observed in hepatitis C.
Future Nutrigenetics: In Search of the Missing Genetic Variation
Authors: Mariman Edwin C.M.
Published: May 2010

Despite considerable effort, genetic analysis of complex disorders and traits, including those related to nutrition, has revealed only a very small part of the expected genetic variation. Missing variation may occur as conditional variation depending on the presence of defined lifestyle factors, as epigenetic variation or as low-moderate effect size variation not detected by mutation screening and genome-wide association studies. Experience with genetic analysis of patients with neural tube defects provides evidence of the existence of the latter type of variation and demonstrates that candidate gene analysis is an efficient approach to discover part of this missing variation. By reviewing the genes with rare and common variation associated with obesity or related parameters, guidelines are proposed for the proper selection of candidate genes. This selection fits into an analytic strategy to deal with the complex and massive data sets expected to arise from the application of routine whole genome sequencing.