Search

Impairment of both insulin and leptin action has been implicated in the pathogenesis of nonalcoholic fatty liver disease. By assessing hepatic triglyceride (TG) stores in response to modulation of leptin action (by leptin infusion), we attempted to determine whether leptin has the major role in hepatic TG accumulation. TG were markedly decreased (by 63%, P<0.05) in young animals treated with leptin. However, this was also associated with improvement in hepatic insulin action (2-fold decrease in HGP during clamp, P<0.05). These effects on hepatic TG stores and insulin action were abolished in old rats who demonstrate leptin resistance. Since these experiments could not discern the role of leptin from the role of hepatic insulin action on hepatic TG stores, we further examined the effect of improvement of hepatic insulin action by visceral fat removal (VF-). Enhancement of hepatic insulin action in old VF-rats was associated with reduced hepatic TG stores (by 64% P<0.01). Because this manipulation may have induced an improvement in leptin action as well, we studied VF removal in a genetically leptin-resistant model (Zucker Diabetic Fatty rats, ZDF). Only in this mode was exclusive improvement of hepatic insulin action by VF removal not associated with reduced hepatic TG stores, suggesting that improved hepatic insulin action is not necessary for modulation of hepatic TG stores. By dissociating action of leptin from that of insulin, we suggest that the failure of leptin action is the major physiological mechanism for hepatic steatosis. [ABSTRACT FROM AUTHOR]

The article highlights a study which examines the association of multiparity with changes in body fat distribution and insulin resistance among women. Chronically catheterized unstressed and awake, age-matched SD rats that were either virgin or retired breeders were studied. It has been found that multiparity is associated with increased visceral adiposity and insulin resistance.

Pregnancy is associated with changes in fat distribution in humans. Age-matched pregnant rats accumulate ∼2 fold more visecral fat (VF) during preganncy. In order to demonstrate the associtaion between increased VF and hepatic insulin resistance we studied virgin (Vir; n=6), pregnant sham-operated(PS; n=6) and age-matched pregnant rats in which VF was surgically removed 1 month prior to mating(PVF-; n=6). Aged-matched, chronically catheterized unstressed rats underwent euglycemic-hyperinsulinemic clamp on 19 of a 22-day gestation. Primed infusions of somatostatin and insulin (3mU⋅non-pregnant kg-1⋅min-1) were given with 3H³-glucose to follow hepatic glucose flux. After clamps, freezed clamp liver samples were collected and FFA and TG content was measured. PS had significantly more visceral fat than VF-(10.0±l.0 and 4.6±0.8, p<0.01). PS had higher basal FFA (3.7±0.4 vs 1.7±0.1 meq/mL, p<0.05) higher FFA at 120 min (1.5±0.2 vs 0.5±0.21 meq/mL, p<0.05) and a trend toward higher hepatic TG content (3.2±0.3 vs 1.9±0.4 mg/g, p=0.06) compared to Vir. During insulin clamp, PS had significantly less insulin-induced hepatic suppression of glucose production (HGP) than Vir (9.3 ±0.5 vs 5.3 ± 1.4 mg/kg/min, p<0.001). By VF removal, we achieved improved in hepatic insulin action, comparable to the level of the Vir group (5.4 ±0.7 vs 5.3±1.4 mg/kg/min, p=0.8). Additionally, VF- had no significant difference in basal FFA (2.0±0.21 meq/mL), FFA at 120 min (0.8±0.21 meq/mL) and hepatic TG content (PVF-=1.3 ± 0.4mg/g) compared to Vir. In summary, because prevention of visceral fat accretion prevent the heptic metabolic abnormaities of pregnancy we suggest it plays a causal role, leading to increased risk of gestational diabetes and T2DM. Because we determined that number and size of pups of VF- rats are similar to PS, we challenge whether insulin resistance plays any positive physiological role in pregnancy. [ABSTRACT FROM AUTHOR]

It has been suggested that macrophages present in adipose tissue are directly involved in the development of the pro-inflammatory state. Pro-inflammatory state is a part of metabolic syndrome and aging. We asked whether aging, independent of changes in body weight or adiposity modulates macrophage content in adipose tissue and the pro-inflammatory properties of macrophages. Three groups of male F344 x BN rats were studied: four months young ad libitum (AL) rats (average body weight 375 g, visceral fat content 5.4 g); 15-months-old AL rats (average body weight 480 g, visceral fat content 18 g); 15-months-old calorie restricted (CR) rats (average body weight 350 g, visceral fat content 5.6 g). Tissue samples were isolated from subcutaneous fat (SF) or visceral fat tissue (VF). Samples were processed by flow cytometric analysis to estimate the percentage of macrophages. Cells were separated into stromal vascular tissue, adipocytes and macrophages and quantitative real-time PCR was performed to determine gene expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in each fraction. Macrophage content per gram tissue in VF and SF was significantly higher in old AL and old CR groups of rats compared to the young rats (p<0.05 and p<0.001 respectively). Furthermore, there was a higher percentage of macrophages in SF compared to VF in both groups of old rats. TNF-α and IL-6 gene expression was 2-fold higher in the macrophage fraction of VF and SF in both old groups compared to young rats (p<0.01). These results suggest that aging itself contributes to the altered biology of the adipose tissue, in addition to adiposity and/or changes in the body composition characteristic of old age. Life-long CR restored a 'young' phenotype of the animals but it did not reverse the age-related phenomenon of macrophage accumulation in the adipose tissue and the higher expression of TNF-α and IL-6, likely contributing to the pro-inflammatory state of aging. [ABSTRACT FROM AUTHOR]

The complement system regulator CD55 was initially found to carry the Cromer blood group system antigens, and its complete loss of function was subsequently revealed to cause a severe monogenic gastrointestinal syndrome characterized by protein-losing enteropathy and susceptibility to venous thrombosis. Here we present homozygosity to the CD55 c.596C>T; p.Ser199Leu variant, which was previously described as the Cromer Dr(a−) genotype, in two Bukharan Jewish CD55-deficiency patients with variable disease severity. We confirm that this missense variant causes aberrant splicing and deletion of 44 bp in exon 5, leading to premature termination and low expression of the CD55 protein. Furthermore, Patient 1 exhibited a mildly abnormal B cell immunophenotyping profile. By population screening we established that this variant is highly prevalent in the Bukharan Jewish population, with a carrier frequency of 1:17, suggesting that many similar patients are un- or mis-diagnosed. The phenotypic variability, ranging from abdominal pain when eating a high-fat diet to the full CD55-deficiency phenotype, is likely related to modifiers affecting the proportion of the variant that is able to escape aberrant splicing. Establishing the diagnosis of CD55-deficiency in a timely manner, even in patients with milder symptoms, may have a critical effect on their management and quality-of-life since treatment with the complement inhibitor eculizumab is highly effective in ameliorating disease manifestations. Awareness of founder mutations within certain populations can further guide genetic testing and prevent a diagnostic odyssey, by placing this CD55 variant high on the differential diagnosis. [ABSTRACT FROM AUTHOR]

Background: Dumping syndrome (DS) is a common complication of bariatric surgery. Treatments include dietary and behavioral changes, as well as pharmacotherapy and revision surgery. All can be costly or hard to adhere to. In recent years, evidence accumulates in favor of endoscopic trans-oral outlet reduction (TORe) as an effective treatment for DS, targeting the pathophysiology of rapid gastric clearance. The objective of this study is to assess the safety and efficacy of TORe for DS in a single referral center. Methods: Patients after bariatric surgery suffering DS were followed, and data were retrospectively analyzed. Diagnosis and post-procedural assessment of DS were made clinically using Sigstad score. During the procedure, the anastomotic rim was cauterized. Afterwards, 2 non-interrupted "8-figure" sutures were placed, resulting in imbrication of additional gastric tissue on top of the anastomosis and narrowing to <1 cm at the end of the procedure. Patients were instructed to keep a liquid diet for 14 days and follow-up continued for 6 months. Results: Between 8/2018 and 9/2019 TORe was carried out in 13 patients (M:F = 3:10) with mean age of 45.1 (range 25–56) and BMI of 33.5 (range 28.1–40.3). Average time since recent surgery was 5.5 years (range 1–9). Mean pre-procedure anastomosis diameter was 25.2 mm (range 15–30) and was reduced to a mean of 5.6 mm (range 5–10). Three patients (23%) were admitted overnight due to inability to drink which resolved spontaneously. No major complications were reported. At 6 months, the Sigstad score was significantly reduced (19.4 ± 3.6 vs 5.2 ± 5.5, P < 0.001), and 11/13 (85%) of patients had a complete resolution of their dumping symptoms. In addition, BMI decreased by a mean of 2.3 kg/m2 (−1 to 7.5, p = 0.002). Conclusion: TORe is a safe and effective treatment for patients suffering dumping syndrome and should be considered early in the treatment of DS. [ABSTRACT FROM AUTHOR]

• Investigating extracellular-matrix (ECM) dynamics during inflammatory disease onset reveals a unique ECM state, which we term the "pre-symptomatic ECM". • The pre-symptomatic ECM is characterized by distinct structural, mechanical and compositional characteristics. • Both subclinical infiltration of immune cells bearing remodeling enzymes and elevated gelatinase activity in the epithelium contribute to the pre-symptomatic ECM. Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, ‎poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular–matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular–matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by subclinical infiltration of immune cells bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular–matrix is general and relevant to a wide range of diseases. [ABSTRACT FROM AUTHOR]

Accordingly, CD55 staining of the patient's cells showed near absent CD55 expression with her carrier mother showing a CD55 MFI of ~ 50% compared with control (Fig. As for a theoretical possible contribution of eculizumab treatment to angiosarcoma development or progression, it is possible that the patient developed her malignancy even prior to initiation of eculizumab treatment and that early symptoms were masked by chronic steroid treatment. Moreover, eculizumab treatment is effective and safe in the long-term treatment of three pediatric CD55-deficiency patients now treated for over 3 years [[3]] (and personal communication). [Extracted from the article]

Background: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy.Methods: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than -20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed.Findings: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13-CT-P13 group and 55 to the CT-P13-infliximab group) and 109 to initiate infliximab (54 to the infliximab-infliximab group and 55 to the infliximab-CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference -4·9% [95% CI -16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13-CT-P13 group, 34 [62%] in the CT-P13-infliximab group, 37 [69%] in the infliximab-infliximab group, and 40 [73%] in the infliximab-CT-P13 group).Interpretation: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease.Funding: Celltrion, Pfizer. [ABSTRACT FROM AUTHOR]

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor-GLP-1 receptor (GIPR-GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil-induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity.

Revisional Bariatric Surgery (RBS) is increasing in popularity. Elderly patients (> 65 years old) are sometimes referred for RBS evaluation. The aim of this study is to evaluate outcomes of elderly patients undergoing RBS. A retrospective analysis of a cohort from a single-tertiary bariatric center. All elderly patients undergoing RBS after restrictive procedures between 2012 and 2022 were included. Thirty Nine patients undergoing RBS were included in the comparative analysis - 23 patients (57.5%) after adjustable gastric banding (s/p LAGB) and 16 patients (40%) after Sleeve Gastrectomy (s/p SG). The mean age and body mass index (BMI) of patients were comparable (67.2 ± 2.8 years and 38.3 ± 7.4, respectively). There was no difference in associated medical problems except reflux which was higher in s/p SG (68% vs. 13%; p < 0.001). The mean time interval between surgeries was 8.7 ± 5.1 years. The surgeries included One anastomosis gastric bypass (n = 22), SG (n = 8) and Roux-en-y gastric bypass (n = 9). Early major complication rates were comparable (4.3% and 12.5%; p = 0.36), and readmission rate was higher in patients s/p SG (p = 0.03). Ninety percent of patients were available to a follow-up of 59.8 months. The mean BMI and total weight loss was 29.2 and 20.3%, respectively with no difference between groups. The rate of patients with associated medical problems at last follow-up was significantly reduced. Five patients (12.5%) underwent revisional surgery due to complications during follow-up. In conclusion, RBS in the elderly is associated with a reasonable complication rate and is effective in terms of weight loss and improvement of associated medical problems in a 5-year follow-up., Competing Interests: Declarations. Conflict of interest: All authors declare they have no potential conflicts of interest or financial ties to disclose. No funding was received for this publication. Ethical approval: All procedures performed in this study were in accordance with ethical standards of the institutional and/or national health research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent does not apply., (© 2024. The Author(s).)

Introduction: In this study, we report a novel therapeutic approach redirecting antigen-specific CD4 + T cells recognizing a hybrid insulin peptide (BDC2.5 T cell receptor (TCR) transgenic CD4 + T cells) to attract and suppress islet-specific CD8 + T cells T cells in the non-obese diabetic (NOD) mouse model, and prevent the development of autoimmune diabetes., Methods: Purified BDC2.5 CD4 + T cells were induced to differentiate into regulatory T cells (Tregs). The Tregs were then electroporated with mRNA encoding chimeric human β 2 microglobulin (hβ 2 m) covalently linked to insulin B chain amino acids 15-23 (designated INS-eTreg) or islet-specific glucose-6-phosphatase related protein (IGRP) peptide 206-214 (designated IGRP-eTreg). Immunoregulatory functions of these engineered regulatory T cells (eTregs) were tested by in vitro assays and in vivo co-transfer experiments with β-cell-antigen-specific CD8 + T cells in NOD.Scid mice or by adoptive transfer into young, pre-diabetic NOD mice., Results: These eTregs were phenotyped by flow cytometry, and shown to have high expression of FoxP3, as well as other markers of Treg function, including IL-10. They suppressed polyclonal CD4 + T cells and antigen-specific CD8 + T cells (recognizing insulin or IGRP), decreasing proliferation and increasing exhaustion and regulatory markers in vitro . In vivo , eTregs reduced diabetes development in co-transfer experiments with pathogenic antigen-specific CD8 + T cells (INS-CD8 + or IGRP-CD8 + cells) into NOD.Scid mice. Finally, when the eTreg were injected into young NOD mice, they reduced insulitis and prevented spontaneous diabetes in the recipient mice., Conclusion: Our results suggest a novel therapeutic strategy to protect NOD mice by targeting antigen-specific cytotoxic CD8 + T cells, using redirected antigen-specific CD4 + Treg cells, to suppress autoimmune diabetes. This may suggest an innovative therapy for protection of people at risk of development of type 1 diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kakabadse, Chen, Fishman, Weinstein-Marom, Davies, Wen, Gross and Wong.)

Cholestatic injuries are accompanied by ductular reaction, initiated by proliferation and activation of biliary epithelial cells (BECs), leading to fibrosis. Sortilin (encoded by Sort1) facilitates IL-6 secretion and leukemia inhibitory factor (LIF) signaling. This study investigated the interplay between sortilin and IL-6 and LIF in cholestatic injury-induced ductular reaction, morphogenesis of new ducts, and fibrosis. Cholestatic injury was induced by bile duct ligation (BDL) in wild-type and Sort1 -/- mice, with or without augmentation of IL-6 or LIF. Mice with BEC sortilin deficiency (hGFAP cre .Sort1 fl/fl ) and control mice were subjected to BDL and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet (DDC) induced cholestatic injury. Sort1 -/- mice displayed reduced BEC proliferation and expression of BEC-reactive markers. Administration of LIF or IL-6 restored BEC proliferation in Sort1 -/- mice, without affecting BEC-reactive or inflammatory markers. Sort1 -/- mice also displayed impaired morphogenesis, which was corrected by LIF treatment. Similarly, hGFAP cre .Sort1 fl/fl mice exhibited reduced BEC proliferation, but similar reactive and inflammatory marker expression. Serum IL-6 and LIF were comparable, yet liver pSTAT3 was reduced, indicating that sortilin is essential for co-activation of LIF receptor/gp130 signaling in BECs, but not for IL-6 secretion. hGFAP cre .Sort fl/fl mice displayed impaired morphogenesis and diminished fibrosis after BDL and DDC. In conclusion, sortilin-mediated engagement of LIF signaling in BECs promoted ductular reaction and morphogenesis during cholestatic injury. This study indicates that BEC sortilin is pivotal for the development of fibrosis., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: OAGB is the third most common bariatric surgery. Biliary reflux (BR) is an inherent complication of this unique anatomy, although there is still controversy regarding its significance and long-term risks including carcinogenesis. To date, there is no effective treatment for BR with conversion to RYGB reserved for refractory patients. TORe is an effective treatment for weight-regain and dumping syndrome after RYGB. We hypothesized that narrowing the anastomosis would decrease the amount of bile refluxate entering the stomach and esophagus in patients with BR symptoms after OAGB and alleviate symptoms. The purpose of this study is to evaluate the efficacy of TORe for the treatment of BR symptoms after OAGB., Materials and Methods: BR was diagnosed clinically in patients after OAGB using the gastroesophageal reflux disease health-related quality of life (GERD-HRQL) instrument after treatment with high-dose proton pump inhibitor (PPI) excluded possible acid reflux. TORe was carried out using a suture pattern that narrowed and elongated the anastomosis. All patients were prospectively followed., Results: Twelve patients, post-OAGB, underwent TORe for BR. Symptoms resolved in 9 (75%) patients. GERD-HRQL score at 6 months declined from an average of 33.7 (SD 1.9) before the procedure to 16.1 (SD 10, p < 0.001). In one case, a small perforation was identified during the procedure and was immediately sutured with no further sequela., Discussion: TORe appears a safe and effective treatment for BR symptoms after OAGB, at least in the short term. Accurate tools for BR diagnosis, a larger cohort, and longer follow-up periods are needed to better show the effectiveness and durability of this treatment option., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Sleeve gastrectomy is one of the most popular bariatric procedures performed. A complication of this surgery is sleeve stenosis, causing significant morbidity and the need for corrective intervention. Endoscopic treatment using pneumatic dilation has evolved as an effective, and minimally invasive, technique to successfully treat this complication. Here we report our experience with endoscopic management of sleeve stenosis at a tertiary bariatric center., Material and Methods: We identified all patients that underwent endoscopic management of sleeve stenosis at a tertiary bariatric center from 2010. We reviewed patient demographics, operative data, interval to endoscopic treatment, and outcomes of pneumatic dilations., Results: Sixty seven patients underwent 130 endoscopic dilations. The majority of these patients were female (71%), and at the time of sleeve gastrectomy average age was 43.3 years (range 18-68 years) and average BMI was 41.5 kg/m 2 (range 31-63 kg/m 2 ). The time interval to first endoscopic procedure was 7.2 months (range 0.75-53 months), with an average of 2 procedures per patient. During the follow-up period, the success rate of endoscopic dilatation was 76.1%, while the remaining 16 patients underwent conversion to gastric bypass. Two patients underwent emergency conversion to gastric bypass for sleeve perforation during the procedure (1.5%). There was a modest weight gain of 3 kg (4.2% total body weight) after sleeve dilatation., Conclusions: Endoscopic management of sleeve stenosis is safe and effective, with a success rate of over 75%. During endoscopic management, there was a 1.5% risk of sleeve perforation requiring emergency surgery. Mild weight regain occurred following endoscopic sleeve dilation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Drug-induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used antiarrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, not all completely understood. We hypothesized that repetitive AMD administration may induce hepatic lipotoxicity not only via effects on the liver but also via effects on adipose tissue. Indeed, repetitive AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue. In adipose tissue, AMD reduced lipogenesis and increased lipolysis. Moreover, AMD treatment induced ER stress and ER stress-dependent lipolysis in 3T3L1 adipocytes in vitro. In the liver, AMD caused increased expression of genes encoding proteins involved in fatty acid (FA) uptake and transfer ( Cd36 , Fabp1 , and Fabp4 ), and resulted in increased hepatic accumulation of free FAs, but not of triacylglycerols. In line with this, there was increased expression of hepatic de novo FA synthesis genes. However, AMD significantly reduced the expression of the desaturase Scd1 and elongase Elovl6 , detected at mRNA and protein levels. Accordingly, the FA profile of hepatic total lipids revealed increased accumulation of palmitate, an SCD1 and ELOVL6 substrate, and reduced levels of palmitoleate and cis -vaccenate, products of the enzymes. In addition, AMD-treated mice displayed increased hepatic apoptosis. The studies show that repetitive AMD induces ER stress and aggravates lipolysis in adipose tissue while inducing a lipotoxic hepatic lipid environment, suggesting that AMD-induced liver damage is due to compound insult to liver and adipose tissue. NEW & NOTEWORTHY AMD chronic administration induces hepatic lipid accumulation by several mechanisms, including induction of hepatic ER stress, impairment of β-oxidation, and inhibition of triacylglycerol secretion. Our study shows that repetitive AMD treatment induces not only hepatic ER stress but also adipose tissue ER stress and lipolysis and hepatic accumulation of free fatty acids and enrichment of palmitate in the total lipids. Understanding the toxicity mechanisms of AMD would help devise ways to limit liver damage.

Aim: To examine whether hepatitis C virus (HCV)-infected patients who carry hypercoagulable mutations suffer from increased rates of liver fibrosis., Methods: We analyzed DNA samples of 168 HCV patients for three common hypercoagulable gene mutations: prothrombin 20210 (PT20210), factor V Leiden (FV Leiden) and methylene tetrahydrofolate reductase (MTHFR). The patients were consecutively recruited as part of the prospective "Fibroscore Study" in France. The effect of the various mutations on the rate of fibrosis was analyzed statistically and was correlated with epidemiological, clinical and biochemical data such as grade and stage of liver biopsies, patients' risk factors for liver cirrhosis, and timing of infection., Results: Fifty two of the patients were categorized as "fast fibrosers" and 116 as "slow fibrosers"; 13% of the "fast fibrosers" carried the PT20210 mutation as compared with 5.5% of the "slow fibrosers", with an odds ratio of 4.76 (P = 0.033; 95% CI: 1.13-19.99) for "fast" liver fibrosis. Carriage of MTHFR or FV Leiden mutations was not associated with enhanced liver fibrosis., Conclusion: Carriage of the PT20210 mutation is related to an increased rate of liver fibrosis in HCV patients.