Target genes regulated by MEG3 were detected with the Dual Lucife

Target genes regulated by MEG3 were detected with the Dual Luciferase reporter system and their expression levels were confirmed using qRT-PCR and Western blotting. Results: In contrast to matched adjacent non-neoplastic tissues, the expression of MEG3 was absent or decreased in most HCC tissues as well as in HepG2 cells. Low expression levels of MEG3 were associated with advanced pathologic stage, tumor size and a relatively

poor prognosis in HCC patients. Hypermethylation of MEG3 differentially methylated regions was identified by MSP in both HCC tissues and HepG2 cells and MEG3 expression was increased with the inhibition of DNA methyltransferase with 5-aza-2′-deoxycytidine treatment. MEG3 was overexpressed by transfection with pcDNA3.1-MEG3 in HepG2 cells. qRT-PCR analysis revealed that MEG3 expression was increased

by 51-fold in HepG2 cells, LBH589 compared with the empty vector group. Overexpression of MEG3 decreased cell proliferation and increased 11% cell apoptosis ratio in vitro. MEG3 activated P53 and ILF-3 in HepG2 cells. Conclusion: Our data suggest that MEG3 is epigenetically silenced due to promoter hypermethylation, which may contribute to the development of HCC. MEG3 plays BMN673 a tumor suppressor role by activating P53 and ILF-3 gene. Key Word(s): 1. MEG3; 2. hepatocellular arcinoma; 3. methylation; 4. prognosis; 5. p53 Presenting Author: LING FEI WU Additional Authors: MENG QI XIANG, WEI DENG, LI XUAN

LIU, XIAO TAO ZHOU, PEI RUI CHEN, LING FEI WU Corresponding Author: LING FEI WU Affiliations: Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University selleck inhibitor Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med Objective: To investigate the role of DNA methyltransferases (DNMTs) and methylation on adenosine (ADO)-induced apoptosis in human hepatocellular carcinoma HepG2 cells. Methods: HepG2 cells were treated with different concentrations of ADO alone or in combination with homocysteine (HCY) for different durations. 5-aza-2′-deoxycytidine (5-Aza-CdR) as a positive control. Cell proliferation inhibition rates were evaluated by CCK8 assay. Cell apoptosis was detected by AnnexinV-FITC/PI staining. The mitochondrial membrane potentials were measured by flow cytometry. The mRNA and protein expression of DNMT1, DNMT3a, DNMT3b, MDM-2, P53, caspase-3, caspase-9 and cytochrome C were detected by qRT-PCR and Western blotting, respectively. The mRNA expression of lncRNA-MEG3 was also detected by qRT-P CR. Results: ADO alone or in combination with HCY significantly suppressed the cell proliferation of HepG2 cells in a dose- and time-dependent manner.

also found TLR4 SNPs rs4986791 and rs960312 were associated with

also found TLR4 SNPs rs4986791 and rs960312 were associated with increased fibrosis risk.[103] Carriage

of Asp299Gly and Thr399Gly is approximately 8% in Caucasian populations, while SNP rs960312 is important for its high prevalence within Asian populations (up to 25%). It has been shown that protective variants lower the apoptotic threshold of hepatocytes, inhibit TLR4 and NFκB signaling, and are associated with greater spontaneous apoptosis of HSCs.[104] By contrast, Eid et al.[105] found that in the post-transplant HCV setting, TLR2 polymorphism Arg753Gln homozygosity was strongly associated with rapid HCV fibrosis progression but found no association between TLR4 polymorphisms and adverse outcomes. The TLR7 gene is located on the X chromosome, and three SNPs in this gene have been identified with > 5% carriage within Caucasian Y-27632 cell line populations: c.1-120T>G (rs2302267), c.32A>T (rs179008, Gln11Leu), and c.2403C>A (rs5743781, Ala448Val).[106] In chronic HCV infection, c.1-120TVemurafenib mouse to explain reduced hepatic fibrosis, as IL-6 has been shown in various studies to be antifibrotic.[92-94] In contrast, c.32A>T was associated with increased susceptibility

to HCV in women, with higher levels of viremia, more rapid selleck disease progression, and failure to respond to interferon-based HCV therapy.[107] TLR7-mediated IFN-α secretion is impaired in these women, while TLR7-mediated IL-6 production is preserved.[108] These data collectively demonstrate that TLR2, TLR4, and TLR7 gene SNP detection may eventually provide potential screening tools for adverse outcomes in HCV-infected patients,

guiding timing of therapy. However, further validation studies are warranted. Given the evidence for impairment of TLR function in HCV infection, restoration of TLR function through TLR agonists is a theoretically attractive approach for potential therapy. In particular, restoration of TLR3-, TLR7-, and TLR9-mediated NK cell and DC interferon secretion so as to improve antigen presentation and T-cell activation is an enticing target for therapy; these effects would not reduce immune responses against other infections, as may be seen if TLR inflammatory pathways were targeted. Importantly, TLR therapies may be less susceptible to viral resistance and broadly active against all HCV genotypes as they do not target HCV proteins directly. There is evidence that TLR7 agonists are effective at HCV suppression. Isotoribine successfully reduced serum HCV levels in phase I trials but unfortunately has been removed from further studies because of adverse events; other TLR7 agonists are under development.

64; p<0001), platelet count <150×103/μL (HR: 769; p<0001), age

64; p<0.001), platelet count <150x103/μL (HR: 7.69; p<0.001), age >60 years (HR: 4.28; p<0.001),

diabetes (HR: 3.96; p<0.001), serum AST level >40 IU/L (HR: 3.79; p<0.001), and serum albumin level <4.0 g/dL (HR: 2.56; P=0.008) as independent risk factors for HCC. Regarding the FIB4-index, 130 NAFLD NVP-BGJ398 supplier patients (1.96%) and 24 (2.54%) AFLD patients were considered to have advanced fibrosis (presence of bridging fibrosis equivalent to NASH stage 3-4), and these estimated advanced fibrotic patients had a significantly higher incidence of HCC than estimated non-advanced fibrotic patients in each group. Conclusions: Excessive alcohol consumption has a considerable effect on hepatocarcinogenesis in fatty liver disease compared with NAFLD. And, non-invasive predictive procedures of liver fibrosis the FIB4-index possibly useful for prediction of high risk group of HCC in fatty liver patients with or without excessive alcohol consumption. Disclosures: Kenji Ikeda – Speaking and Teaching: Dainippon Sumitomo Pharmaceutical Company Norio Akuta – Patent Held/Filed: SRL. Inc. Hiromitsu Kumada – Speaking and Teaching: Bristol-Myers Squibb,Pharma International The following people have nothing to disclose: Yusuke Kawamura, Yasuji Arase, Taito Fukushima, Tasuku Hara, Tetsuya Hosaka, Masahiro Kobayashi, Satoshi Saitoh, Hitomi

Sezaki, Fumitaka Suzuki, Yoshiyuki Suzuki, Yuki Ohmoto, Kazuhisa Amakawa, Hiroshi Tsuji Introduction) Smoking increases the risk of cardiovascular diseases and lung cancer. However, the effect selleck inhibitor of smoking on progression and carcinogenesis in liver diseases such as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver diseases (ALD) has not been clear. In this study, we investigated the relationship between smoking and the clinical features in NAFLD, the rates of hepatocellular carcinoma (HCC) and extra-hepatic

malignancies. Patients and Methods) 1) Three hundred forty-six NAFLD patients who underwent liver biopsy were divided into three groups: a non-smoking group (212 patients; mean age 52, male 63%), a past-smoking group (65 patients; mean age 54, male 66%) and a present-smoking group (69 patients; mean age 52, male 65%). Among the three groups, lifestyle-related diseases prevalence, blood test results and liver histological findings were compared. 2) Seventy-two patients with NAFLD liver cirrhosis (NAFLD-LC) and 85 patients with ALD liver cirrhosis (ALD-LC) were enrolled. The occurrence rate of HCC and extrahepatic malignancies were investigated. Results)1. Age and gender were almost the same among the three groups of NAFLD. Serum liver function test results (albumin, total bilirubin, AST, ALT, g-GTP, Platelet counts, prothrom-bin time) were not significantly different. However, HbA1C in the present-smoking groups was significantly higher (mean HbA1C<%>: present-smoking 6.6; past-smoking 5.9; nonsmoking 5.9).

In a multiracial country like Malaysia, where we can compare the

In a multiracial country like Malaysia, where we can compare the changes between different Asian races, Rosaida and Goh, in an earlier study identified Indian race as a risk factor for GERD and erosive reflux esophagitis.22 In a time trend study by the same group, Goh et al. recorded a significantly higher rise in esophagitis over a 10-year interval amongst Indians (2.4%–8.1%) compared to Chinese (1.7%–6.4%) and Malays (1.5%–3.7%).68

In another study, Rajendra et al. showed a distinct predisposition to develop Barrett’s esophagus in Indian patients and further showed a predominance of HLA B7 subtype amongst Indians with Barrett’s esophagus.52 While environmental influence would remain fairly consistent across all races, these differences identify Indians as a genetically susceptible GPCR Compound Library race to the influence of LBH589 environmental

factors in the development of GERD. Interestingly a study from the UK lends support to this notion by identifying South Asian race (Indian) versus White Caucasians as a risk factor for GERD.120 While heartburn is the cardinal symptom of GERD and is well recognized in the West, the situation is distinctly different in our part of the world. For example, there is no word in the Chinese vernacular language to describe this symptom. Spechler et al.121 in a survey of outpatients attending clinics in the Boston area, USA, discovered that the majority of patients of East Asian origin did not understand the symptom of heartburn. In the Asian setting many patients complain of chest discomfort which has been loosely classified as non-cardiac chest pains.121–124“Wind” is also a predominant complaint of many patients with reflux disease.125 In many Southeast Asian countries, Malay patients use vernacular terms which

do not translate exactly to the original terms of heartburn and acid regurgitation.126 Endoscopy is a widely used tool for diagnosis find more of upper gastrointestinal complaints and will continue to be so. More Asian centers are now utilizing pH measurements as an adjunct to clinical and endoscopic diagnosis. The advent of the “catheterless” Bravo capsule has allowed more tertiary centers throughout the region to utilize pH measurements. Bilitec and impedance measurements are also more readily available nowadays in many Asian centers. The past 20 years has seen the emergence of reflux disease as an important disease in Asia. Although, it generally remains a mild disease in Asian patients, we know from the Western experience that serious complications can arise, chiefly Barrett’ esophagus and associated adenocarcinoma of the cardio-esophageal junction. Continued efforts must be made to ensure an accurate description of the disease burden and to track the evolution of the disease over time and across the whole region. In particular, translated and validated questionnaires should be utilized for surveys of GERD symptoms in the population.

Of the 185 patients, 89 had serum samples stored in the serum ban

Of the 185 patients, 89 had serum samples stored in the serum bank. These samples were retrieved for virological analysis. Regression analysis indicated that the HBV-DNA levels derived from liver samples were significantly correlated with those from serum samples (regression coefficient 0.0439; 95% CI 0.0391-0.0487; P < 0.001) (Fig. 5). In a subgroup of patients, a large amount of HBV-DNA was found in the liver tissue, but a relatively lower HBV-DNA concentration was detected in the serum sample (Fig. 5, squares [n = 8]), suggesting a defect of viral secretion. In another subgroup of patients, a small amount of

HBV-DNA Selleckchem SCH772984 was found in the liver tissue, but a high HBV-DNA concentration Peptide 17 datasheet was detected in the serum sample (Fig. 5, circles [n = 5]), indicating an extraordinarily high efficiency of viral secretion. Using cases without abnormal secretion efficiency, a regression equation was obtained to convert tissue to serum HBV-DNA levels for practical

application (Fig. 5). Sequence analysis for precore stop codon mutation, BCP mutation, and genotype revealed discrepancies between serum-derived and tissue-derived data in 11 patients, including eight and seven discrepancies for precore stop codon mutation and BCP mutation, respectively. Interestingly, of these 11 patients, six were in either of the two abnormal subgroups (Fig. 5, solid squares and circles). Discrepancies in the detection selleck inhibitor of large fragment pre-S mutants occurred in 18 patients. The mutants were detected in the serum but not the tissue samples in 11 of them, whereas in the remaining seven patients, the mutants were detected in the tissue but not the serum samples. Five of these seven patients were in the subgroup with secretion defect (Fig. 5, asterisks).

Of the 89 patients with available serum samples, short fragment pre-S deletion mutants were detected in the liver tissues in nine of them (PSMUT 1-8 and 11). Of these mutants, seven were also detected in the serum samples (PSMUT 1-5, 7, 8). The remaining two were in the subgroup with secretion defect (Fig. 5, pound symbols). Despite HCC’s multifactorial etiology, HBV remains the major causative factor in Southeast Asia, where HBV is highly prevalent.26 By characterizing the HBV genome sequences derived from patients’ serum, several studies have illustrated that various virological factors are closely associated with hepatocarcinogenesis, including serum HBV-DNA concentration, genotype, and the presence of a basal core promoter mutation.27 Furthermore, by performing cell-based and animal-based experiments, several viral proteins have been shown to be implicated in the oncogenesis of liver cancer, including X proteins, large surface proteins, and pre-S deletion mutants.

The perceived risk of bleeding associated with sport, however, ma

The perceived risk of bleeding associated with sport, however, may be overstated. To date three studies have examined the association between physical activity and bleeding outcomes in

children with haemophilia [27, 61, 62]. Two studies found no association between level of physical activity and bleeding rates or joint outcomes [61, 62]. A further study which examined the temporal relationship between physical activity and bleeding and adjusted selleck screening library for clotting factor levels in the blood found a moderate transient increase in bleeding risk associated with vigorous physical activity (odds ratio 2.7 for ‘moderate-risk sports’ and 3.7 for ‘high-risk sports’) [27]. Table 2 [27] denotes sporting activities according to their relative risks of bleeding when compared with the inactive state or light activity such as walking. As the proportion of time spent in vigorous activity is usually relatively small compared to Carfilzomib mouse the total number of hours in a week, the increase in absolute bleeding risk associated with physical activity is likely to be small. It is possible, however, that sporting activity impacts on joint health in the absence of clinically detectable bleeds. To date, this association has not been

determined. As expected, rates of bleeding are inversely related to pre-existing levels of clotting factor activity. While the reporting of relative risk may help PWH balance the benefits and risks of sports participation, assessing bleeding risk involves more than just odds ratios. All bleeds are not equal. Take the example of an adolescent boy who wants to play rugby union. While the transient increase in risk of bleeding with this sport is comparable to a sport such as ice skating, the possibility of a serious intra-cerebral bleed is likely to be greater in rugby so this risk might be considered to be unacceptable vs. ice skating which has the same relative risk. The only evidence-based preventative strategy to reduce bleeding episodes

in sport is the administration of prophylactic clotting factor. For every 1% increase in clotting factor level, there is a 2% reduction in bleeding click here risk [27]. There is still debate regarding optimal prophylactic schedules and dosing. In practice, many PWH schedule their prophylaxis around periods of high activity or sport. The efficacy and cost-effectiveness of this approach vs. standard prophylactic dosing regimens needs to be further evaluated in a randomized control trial. Unfortunately, much of the world’s population still has no access to prophylactic clotting factor and this is reflected in the low rates of sports participation and poor fitness levels among PWH in these countries [59]. The impact of the extended half-life products, currently undergoing clinical trials, is cause for optimism in PWH who play sport.

It is well known that mRNAs with PTCs are quickly destroyed by th

It is well known that mRNAs with PTCs are quickly destroyed by the nonsense-mediated mRNA decay (NMD) pathway, which prevents the expression

of truncated proteins [7]. We identified a heterozygous mutation (Asp409del) located in the catalytic domain of FX in the proband. Both coagulation assay and in vitro expression analysis indicated that the mutation was associated with the CRM+ phenotype. The phenotypic features of CRM+ FX deficiency can be heterogeneous. Although in the majority of patients there are defects in both the intrinsic and extrinsic systems, defects only or predominantly in the intrinsic and LDK378 extrinsic pathway have been reported in several studies [8, 9]. The Asp409del mutation described here has defects in both the intrinsic and extrinsic systems. In addition, the amidolytic activity level based on RVV assays was decreased significantly, indicating that enzymatic activity of the mutant was lost. Previous investigations

have revealed that metal ion-binding sites in FXa are not only energetically but also allosterically XL765 mouse linked [10, 11]. Na+ can allosterically modulate the activity and specificity of FXa by binding to four key residues (Arg222, Lys224, Try185, and Asp185a) in loops 221–225 and 185–189. The crystal structure of FXa suggests that the Na+-binding loop, the catalytic pocket of the enzyme, and the FVa-binding helix (residues 163–170) are quite near one another in space and interact with each other to bind or cleave the substrate. In this study, structural molecular modelling showed that the Asp409del mutant could markedly alter the conformation of the 185–189 loop and impair binding of the loop to Na+, leading to a loss of FXa enzymatic activity. In summary, we report here two novel causative mutations (IVS5+1G>A and Asp409del) in the F10 gene, which result in severe FX deficiency. The splice-site IVS5+1G>A variant causes an absence of the abnormal transcript allele due to the NMD pathway. The Asp409del mutation leads to a loss of FXa function rather than the impairment of

mutant FX expression. This report may therefore provide insight into the underlying pathogenesis of inherited FX deficiency. We deeply appreciate Dr. Cheng Luo and Dr. Keqin Kathy Li for their help in the modelling analysis of mutant FXa. The selleck inhibitor authors stated that they had no interests which might be perceived as posing a conflict or bias. “
“Summary.  With the introduction of safe and effective factor VIII/IX-bypassing agents – recombinant activated factor VII (rFVIIa) and plasma-derived activated prothrombin complex concentrates (pd-APCC) – elective orthopaedic surgery (EOS) is a viable option for haemophilia patients with inhibitors. We report a series of patients with haemophilia and inhibitors undergoing EOS between 1997 and 2008 using bypassing agents to provide haemostatic cover.

6) A modification of the fluorescence protease assay also was pe

6). A modification of the fluorescence protease assay also was performed in which freshly prepared protease from replicons was used in place of recombinant protease, as described by Yu et al.21 (Fig. 5D). The results of these experiments were similar to those with the recombinant enzyme, although inhibition of the endogenous AP24534 cost protease required slightly higher concentrations of BV than the recombinant enzyme, possibly because of conversion of BV to BR by endogenous BVR in the microsomes. The kinetics of BV inhibition of NS3/4A protease was assessed on Lineweaver-Burk plots (Fig. 6A). These data indicated that

BV competitively inhibits NS3/4A protease, based on the characteristic increase in slope with higher concentrations of inhibitor. Slopes (Km/V) and y intercepts (1/Vmax) of the primary reciprocal plots were then used to make secondary plots (Fig. 6B, C)

to estimate Ki and Ki′, respectively, as general indices of competitive and noncompetitive inhibition. Note that plots of BV versus 17-AAG concentration either 1/Vap or Km/V showed highly significant linearity, (r1 = 0.975 and r2 = 0.979 respectively, p < 0.005), suggesting that BV has both noncompetitive and competitive inhibitor activity for NS3/4A protease (Ki′ = 1.1 and Ki = 0.6 μM, respectively). BV is rapidly reduced to BR by the soluble enzyme BVR (Fig. 1). We hypothesized that knockdown of BVR expression would result in increased antiviral activity for BV by diminishing its conversion to the less potent BR. Preliminary WB showed that knockdown of BVR was highly efficient and led to more than 80% reduction of BVR expression in both replicon lines (Fig. 7A). The antiviral activity of BV was significantly enhanced by BVR knockdown compared with control (scramble) RNA knockdown (Fig. 7B, left panel, p < 0.01). In contrast, knockdown of BVR before incubation of replicons with BR had no significant effect on the relatively modest antiviral

activity of BR (Fig. 7B, right panel). Taken together, these data support the concept that BVR knockdown augments the check details antiviral activity of BV by arresting its conversion to BR and thereby maintaining higher intracellular levels of BV. Because interferon remains a cornerstone of HCV therapy, we examined the effects of BV on the antiviral activity of α-interferon. As shown in Fig. 8, BV had a clear additive effect when exposed to cells in the presence of interferon. These findings indicate that BV does not appear to compromise the action of interferon, but rather to enhance it. They also raise the possibility that the BV or stable derivatives could be used as antiprotease agents in combination with interferon. Heme oxygenase catalyzes the breakdown of heme to equimolar quantities of BV, iron, and carbon monoxide.

4 Lipid extracts obtained via the Folch procedure23 from 3 mL of

4 Lipid extracts obtained via the Folch procedure23 from 3 mL of LVPs or from 500 μL of each lipoprotein fraction

were separated by thin-layer chromatography (TLC) on Silica Gel G60 plates (Merck, Darmstadt, Germany) with hexane/diethyl ether/acetic acid (60/40/1, vol/vol) solvents. Phospholipid and triacylglycerol were scraped off the plate, and the molecular species composition of phospholipids separated by high-performance liquid chromatography (HPLC) on a silica-DIOL column (4 × 250 mm, Agilent 1100) was analyzed via electrospray ionization/tandem LEE011 mass spectrometry (Q-Trap 2000, Applied Biosystems). Phospholipid classes were eluted subsequently from HPLC as a function of the headgroup polarity using the solvent mixture hexane/isopropanol/aqueous Selleckchem Autophagy Compound Library ammonium acetate 5 mM 62.8/34.8/2.4 at the rate of 100 μL/minute. Experimental details have been discussed in recent reviews.24, 25 The method was set to detect the precursors (i.e., the parent phospholipids) of a characteristic fragment ion of each polar headgroup. Mass spectra were processed with Analyst software (v1.4.2, Applied Biosystems).

Assignment of the structure to mass peaks and deisotopization correction were performed with LIMSA software26 using a library prepared for the serum circulating lipids. Analysis of fatty acids in the triacylglycerol fraction separated by TLC (silica G25; solvent mixture hexane/methyl ether/formic acid: 80/20/2 vol/vol) was achieved by GC separation of methyl esters prepared by acid transmethylation according to Christie WW.27 Separation was achieved on a Carbowax 20 M capillary column (0.25 mm, 30 m, Quadrex) fitted on a Thermo-Electron 8000 GC chromatograph. A total of 20 μL of see more protein A–coated magnetic beads (Miltenyi Biotec) were incubated at room temperature with

1 mL of LDF in PBS with gentle rocking for 30 minutes. Samples were then passed through one magnetic column (Miltenyi Biotec) and washed with 2 mL of PBS and then with buffers of decreasing pH (successively, 300 μL of 0.1 M tris-acetate buffer pH 5.0, pH 4.0, and pH 3.0). Each collected fraction was immediately neutralized by addition of 0.1 N NaOH. Fractions eluted at pH 4.0 were used to stain the western blotting membrane. Immediately after preparation, LDFs or LVP fractions were collected in Laemmli buffer and denatured at 95°C for 5 minutes and kept at −20°C until analysis. Positive controls for E1 and E2 were obtained from lysates of cells expressing HCV glycoproteins or from supernatants of E1/E2-Caco2 differentiated cells,20 collected into Laemmli buffer, denatured, and conserved as described above. Samples were fractionated via sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene fluoride membrane.

113 This can lead to diet-induced steatosis, dyslipidemia, and bo

113 This can lead to diet-induced steatosis, dyslipidemia, and both

insulin and leptin resistance.114 Rimonabant, the prototypic CB1R antagonist, reduced hepatic steatosis and improved dyslipidemia in fa/fa diabetic Hippo pathway inhibitor rats, disproportional to effects on food intake.116 This preliminary observation led to the suggestion that pharmacological approaches to metabolic regulation could have beneficial effects in NAFLD/NASH.116,117 Unfortunately, clinical development of Rimonabant as an anti-obesity agent was discontinued because of a high frequency of depression. Other systems involved in both CNS and peripheral metabolic regulation include NPY and melanocortin.118,119 Thus, stress in rodents releases NPY

from sympathetic nerves. In turn, this up-regulates NPY and its Y2 receptor in abdominal fat by a glucocorticoid-dependent mechanism, resulting in abdominal obesity.118 There is also evidence that blockade of CNS melanocortin receptors (MCR) triggers mobilization of lipid uptake, triglyceride synthesis and fat accumulation in WAT, changes that are independent of food intake.119 This indicates that loss-of-function mutations in MC4R, which have been associated with human obesity, may affect both CNS and peripheral metabolic regulation in see more favor of adiposity. One reason for earlier controversies about NAFLD and NASH is that not all affected patients are obese, although we contend that most are either over-weight or ‘metabolically obese, normal weight’.120 From a burgeoning literature [reviewed in 7,121], the most consistent relationships with NASH have been between central obesity, reflecting visceral adiposity, and insulin resistance. Anthropometric indicators of visceral (central) obesity (VAT), such as waist circumference, have been bolstered by determination of hepatic triglyceride selleck chemical stores using MRS.70,122 Among morbidly obese individuals, steatosis correlates directly with VAT,122 while correlations with subcutaneous adipose tissue (SAT)

stores are less clear, with inconsistent results between studies (some positive, others no correlation).123–126 The relationship between central obesity and NAFLD/NASH is consistent with the proposal that metabolically unhealthy fat is what leads to insulin resistance and cardiovascular disease,127–129 as supported by the strong relationship between central obesity and cardiovascular death and even all-cause mortality.130,131 In non-obese subjects, the relationship between waist circumference and NAFLD/NASH is less clear. Musso and colleagues compared non-obese, non-diabetic NASH patients to controls; there was no difference in waist circumference or waist-hip ratio.