Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease

Background: Type-2 diabetes mellitus (T2DM) is a risk factor for progressive non-alcoholic fatty liver disease (NAFLD). Drugs commonly prescribed in patients with T2DM may affect liver histology by interfering with lipid metabolism and insulin resistance/secretion. Aim: We studied if statins or antidiabetic agents were associated with non-alcoholic steatohepatitis (NASH) and significant fibrosis (SF). Methods: We performed a cross-sectional study of 346 diabetics with biopsy-proven NAFLD. T2DM was defined as fasting glucose ≥7 mmol/L or glycated haemoglobin ≥6.5% and/or use of antidiabetics. NASH was defined according to the FLIP algorithm and SF as F2-4 Kleiner's stages. Results: 84% of patients were on antidiabetic therapy and 45% on statins. NASH and SF were present in 57% and 48% of patients. Statin-treated patients were older, more frequently male and with poorer glycaemic control despite more frequent antidiabetic therapy than those without statins; however, the prevalence of NASH (57%vs56%, p=0.868) and SF (48%vs48%, p=0.943) was not different between statin users and non-users. NASH was more common in patients on metformin or insulin than in those not treated with these drugs (60% vs47%, p=0.026; 68%vs53%, p=0.017). SF was more common in those treated with sulfonylureas (57% vs44%, p=0.030). Multivariate analyses confirmed that use of statins was independently and negatively associated with both NASH (OR (95% CI) 0.57 (0.32 to 1.01), p=0.055) and SF (OR (95% CI) 0.47 (0.26 to 0.84), p=0.011). Moreover, we found independent associations between insulin use and NASH (OR (95% CI) 2.24 (1.11 to 4.54), p=0.025) and sulfonylureas use and SF (OR (95% CI) 2.04 (1.11 to 3.74), p=0.022). Conclusions: Several medications used in patients with diabetes are differently associated with NAFLD histology. Statin use is negatively associated, while insulin and sulfonylureas are positively associated with NASH and SF. A wider use of statins may be warranted in this high-risk population

Accumulation and Changes in Composition of Collagens in Subcutaneous Adipose Tissue After Bariatric Surgery

International audienceExtracellular matrix (ECM) in sc adipose tissue (scAT) undergoes pathological remodeling during obesity. However, its evolution during weight loss remains poorly explored.Objective:The objective of the investigation was to study the histological, transcriptomic, and physical characteristics of scAT ECM remodeling during the first year of bariatric surgery (BS)-induced weight loss and their relationships with metabolic and bioclinical improvements.Design, Setting, Patients, and Interventions:A total of 118 morbidly obese candidates for BS were recruited and followed up during 1 year after BS.Main Outcome Measures:scAT surgical biopsy and needle aspiration as well as scAT stiffness measurement were performed in three subgroups before and after BS. Fourteen nonobese, nondiabetic subjects served as controls.Results:Significantly increased picrosirius-red-stained collagen accumulation in scAT after BS was observed along with fat mass loss, despite metabolic and inflammatory improvements and undetectable changes of scAT stiffness. Collagen accumulation positively associated with M2-macrophages (CD163+ cells) before BS but negatively afterward. Expression levels of genes encoding ECM components (eg, COL3A1, COL6A1, COL6A2, ELN), cross-linking enzymes (eg, lysyl oxidase [LOX], LOXL4, transglutaminase), metalloproteinases, and their inhibitors were modified 1 year after BS. LOX expression and protein were significantly decreased and associated with decreased fat mass as well as other cross-linking enzymes. Although total collagen I and VI staining decreased 1 year after BS, we found increased degraded collagen I and III in scAT, suggesting increased degradation.Conclusions:After BS-induced weight loss and related metabolic improvements, scAT displays major collagen remodeling with an increased picrosirius-red staining that relates to increased collagen degradation and importantly decreased cross-linking. These features are in agreement with adequate ECM adaptation during fat mass loss- See more at: http://press.endocrine.org/doi/10.1210/jc.2015-3348#sthash.PLeUvzKd.dpu

Inflammatory Pathway Genes Belong to Major Targets of Persistent Organic Pollutants in Adipose Cells

Background: Epidemiological studies emphasize the possible role of persistent organic pollutants (POPs) in obesity and the metabolic syndrome. These pollutants are stored in adipose tissue (AT)

Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity

Analysis of the transcriptomic signature of white adipose tissue in obese human subjects revealed increased interstitial fibrosis and an infiltration of inflammatory cells into the tissue

Liquid Chromatography-Mass Spectrometry-Based Parallel Metabolic Profiling of Human and Mouse Model Serum Reveals Putative Biomarkers Associated with the Progression of Nonalcoholic Fatty Liver Disease

Keywords: NAFLD, steatosis, NASH, metabolomics, biomarkers. FOOTNOTE

Le tissu adipeux

L’existence d’un état inflammatoire chronique de bas niveau dans l’obésité pouvant intervenir dans la physiopathologie de la maladie et de ses nombreuses complications est bien établie. Le tissu adipeux lui-même est un site d’inflammation où s’accumulent des macrophages. Dans cette synthèse, nous décrivons les données expérimentales et cliniques qui ont permis d’élucider certains des mécanismes cellulaires et moléculaires impliqués dans la colonisation du tissu adipeux par les macrophages obtenus à partir de précurseurs monocytaires. Les macrophages sont des cellules dont le phénotype varie suivant l’état du microenvironnement. Dans l’obésité, ils peuvent exercer des effets délétères via la production de molécules pro-inflammatoires, mais contribuent également à l’homéostasie du tissu adipeux face aux changements de la masse grasse. Une autre conséquence de l’inflammation du tissu adipeux est la présence d’une fibrose dont la genèse et les conséquences sont encore mal connues. L’identification de mécanismes potentiellement protecteurs, tels que la neutralisation immunologique de certains types de lymphocytes ou encore le contrôle transcriptionnel des gènes de l’inflammation, pourrait suggérer de nouvelles perspectives thérapeutiques pour limiter l’inflammation dans le tissu adipeux

Relevance of omental pericellular adipose tissue collagen in the pathophysiology of human abdominal obesity and related cardiometabolic risk

Background: Adipose tissue fibrosis is a relatively new notion and its relationship with visceral obesity and cardiometabolic alterations remains unclear particularly in moderate obesity. Objective: Our objective was to examine if total and pericellular collagen accumulation are relevant for the pathophysiology of visceral obesity and related cardiometabolic risk. Subjects and methods: Omental (OM) and subcutaneous (SC) fat surgical samples were obtained in 56 women (age: 47.2±5.8 years; BMI: 27.1±4.4kg/m2 ). Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography, respectively. Total and pericellular collagen were measured using picrosirius red staining and CD68+ cells, a marker of total macrophages, as well as CD163+ cells, a marker of M2-macrophages, were identified using immunohistochemistry. Results: We found that only pericellular collagen percentage, especially in OM fat, was associated with higher BMI, body fat mass and adipose tissue areas as well as lower radiologic attenuation of VAT and altered cardiometabolic risk variables. Strong correlations between peri-adipocyte collagen percentage and total or M2-macrophages percentage were observed in both depots. Total collagen percentage in either compartment was not related to adiposity, fat distribution or cardiometabolic risk. Conclusion: As opposed to whole-tissue based assessments of adipose tissue fibrosis, collagen deposition around the adipocyte, especially in the OM fat compartment is related to total and regional adiposity as well as altered cardiometabolic risk profile

Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity

International audienceBackground & AimsNonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis.MethodsSystemic blood before and 12 months post bariatric surgery along with portal blood and adipose tissue lipid efflux collected at the time of surgery from obese women were analyzed (9 structural classes, 150 species).ResultsIncreased concentrations of several Glycerophosphocholines (PC), Glycerophosphoethanolamines (PE), Glycerophosphoinositols (PI), Glycerophosphoglycerols (PG), Lyso-Glycerophosphocholines (LPC), and Ceramides (Cer) were detected in systemic circulation of NASH subjects. Weight loss post-surgery (12 months) improved the levels of liver enzymes, as well as several lipids, but most PG and Cer species remained elevated. Analysis of lipids from hepatic portal system at the time of surgery revealed limited lipid alterations compared to systemic circulation, but PG and PE classes were found significantly increased in NASH subjects. We evaluated the contribution of visceral adipose tissue to lipid alterations in portal circulation by measuring adipose tissue lipid efflux ex vivo, which demonstrated only minor alterations in NASH subjects. Interestingly, integration of clinical and lipidomic data (portal and systemic) led us to define a NASH signature in which lipids and clinical parameters are equal contributorsConclusionCirculatory (portal and systemic) phospholipid profiling and clinical data defines NASH signature in morbid obesity. We report weak contribution of visceral adipose tissue to NASH-related portal lipid alterations, suggesting possible contribution from other organs draining into hepatic portal system