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Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease

van Son, K.C. (author), Verschuren, L. (author), Hanemaaijer, R. (author), Reeves, H. (author), Takkenberg, R.B. (author), Drenth, J.P.H. (author), Tushuizen, M.E. (author), Holleboom, A.G. (author)

Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune...

article 2023

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(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet–Induced Hepatic Steatosis

Gayban, A.J.B. (author), Souza, L.A.C. (author), Cooper, S.G. (author), Regalado, E. (author), Kleemann, R. (author), Earley, Y.F. (author)

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic...

article 2023

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The Human Milk Oligosaccharide 2'-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

Gart, E. (author), Salic, K. (author), Morrison, M.C. (author), Giera, M. (author), Attema, J. (author), de Ruiter, C. (author), Caspers, M.P.M. (author), Schuren, F. (author), Bobeldijk-Pastorova, I. (author), Heer, M. (author), Qin, Y. (author), Kleemann, R. (author)

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2'-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant...

article 2022

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Correction to: Toxicogenomics directory of chemically exposed human hepatocytes

Grinberg, M. (author), Stöber, R.M. (author), Edlund, K. (author), Rempel, E. (author), Godoy, P. (author), Reif, R. (author), Widera, A. (author), Madjar, K. (author), Schmidt-Heck, W. (author), Marchan, R. (author), Sachinidis, A. (author), Spitkovsky, D. (author), Hescheler, J. (author), Carmo, H. (author), Arbo, M.D. (author), van de Water, B. (author), Wink, S. (author), Vinken, M. (author), Rogiers, V. (author), Escher, S. (author), Hardy, B. (author), Mitic, D. (author), Myatt, G. (author), Waldmann, T. (author), Mardinoglu, A. (author), Damm, G. (author), Seehofer, D. (author), Nüssler, A. (author), Weiss, T.S. (author), Oberemm, A. (author), Lampen, A. (author), Schaap, M.M. (author), Luijten, M. (author), van Steeg, H. (author), Thasler, W.E. (author), Kleinjans, J.C.S. (author), Stierum, R.H. (author), Leist, M. (author), Rahnenführer, J. (author), Hengstler, J.G. (author)

Correction to: Arch Toxicol (2014) 88:2261–2287 https://doi.org/10.1007/s00204-014-1400-x.

article 2022

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Minor Changes in the Composition and Function of the Gut Microbiota During a 12-Week Whole Grain Wheat or Refined Wheat Intervention Correlate with Liver Fat in Overweight and Obese Adults

van Trijp, M.P.H. (author), Schutte, S. (author), Esser, D. (author), Wopereis, S. (author), Hoevenaars, F.P.M. (author), Hooiveld, G.J.E.J. (author), Afman, L.A. (author)

Background: Whole grain wheat (WGW) products are advocated as a healthy choice when compared with refined wheat (RW). One proposed mechanism for these health benefits is via the microbiota, because WGW contains multiple fibers. WGW consumption has been proposed to ameliorate nonalcoholic fatty liver disease, in which microbiota might play a role...

article 2021

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Longitudinal characterization of diet-induced genetic murine models of non-alcoholic steatohepatitis with metabolic histological and transcriptomic hallmarks of human patients

Abe, N. (author), Kato, S. (author), Tsuchida, T. (author), Sugimoto, K. (author), Saito, R. (author), Verschuren, L. (author), Kleemann, R. (author), Oka, K. (author)

Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disease in the Western world. Currently, only a few animal models show both the metabolic and histological features of human NASH. We aimed to explore murine NASH models in a time dependent manner that exhibit metabolic, histological and transcriptomic hallmarks of human NASH. For this...

article 2019

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Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis

Salic, K. (author), Gart, E. (author), Verschuren, L. (author), van Duyvenvoorde, W. (author), Wong, K.E. (author), Keijer, J. (author), Bobeldijk-Pastorova, I. (author), Wielinga, P.Y. (author), Kleemann, R. (author)

Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment...

article 2019

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Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD

Gart, E. (author), Souto Lima, E. (author), Schuren, F, (author), de Ruiter, C.G.F. (author), Attema, J. (author), Verschuren, L. (author), Keijer, J. (author), Salic, K. (author), Morrison, M.C. (author), Kleemann, R. (author)

Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of...

article 2019

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A 12-wk whole-grain wheat intervention protects against hepatic fat: The Graandioos study, a randomized trial in overweight subjects

Schutte, S. (author), Esser, D. (author), Hoevenaars, F.P.M. (author), Hooiveld, G.J.E.J. (author), Priebe, M.G. (author), Vonk, R.J. (author), Wopereis, S. (author), Afman, L.A. (author)

Background: Whole-grain wheat (WGW) is described as nutritionally superior to refined wheat (RW) and thus advocated as the healthy choice, although evidence from intervention studies is often inconsistent. The liver, as the central organ in energy metabolism, might be an important target organ for WGW interventions. Objective: The aim of this...

article 2018

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Key Inflammatory Processes in Human NASH Are Reflected in Ldlr-/-.Leiden Mice: A Translational Gene Profiling Study

Morrison, M.C. (author), Kleemann, R. (author), van Koppen, A. (author), Hanemaaijer, R. (author), Verschuren, L. (author)

Introduction: It is generally accepted that metabolic inflammation in the liver is an important driver of disease progression in NASH and associated matrix remodeling/fibrosis. However, the exact molecular inflammatory mechanisms are poorly defined in human studies. Investigation of key pathogenic mechanisms requires the use of pre-clinical...

article 2018

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Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age

Rusli, F. (author), Boekschoten, M.V. (author), Borelli, V. (author), Sun, C. (author), Lute, C. (author), Menke, A.L. (author), van den Heuvel, J. (author), Salvioli, S. (author), Franceschi, C. (author), Müller, M. (author), Steegenga, W.T. (author)

Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver-specific responses caused by a diet switch to a medium-fat (MF) diet in 24-month-old lifelong, CR-exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine...

article 2018

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Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

van Koppen, A. (author), Verschuren, L. (author), van den Hoek, A.M. (author), Verheij, J. (author), Morrison, M.C. (author), Li, K. (author), Nagabukuro, H. (author), Costessi, A. (author), Caspers, M.P.M. (author), van den Broek, T.J. (author), Sagartz, J. (author), Kluft, C. (author), Beysen, C. (author), Emson, C. (author), van Gool, A.J. (author), Goldschmeding, R. (author), Stoop, R. (author), Bobeldijk-Pastorova, I. (author), Turner, S.M. (author), Hanauer, G. (author), Hanemaaijer, R. (author)

Background & Aims: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for...

article 2017

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A casein hydrolysate based formulation attenuates obesity and associated non-alcoholic fatty liver disease and atherosclerosis in LDLr-/-.Leiden mice

Schoemaker, M.H. (author), Kleemann, R. (author), Morrison, M.C. (author), Verheij, J. (author), Salic, K. (author), van Tol, E.A.F. (author), Kooistra, T. (author), Wielinga, P.Y. (author)

Background: Obesity frequently associates with the development of non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Chronic inflammation in white adipose tissue (WAT) seems to be an important driver of these manifestations. Objective: This study investigated a combination of an extensively hydrolyzed casein (eHC), docosahexaenoic...

article 2017

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Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes

Liang, W. (author), Verschuren, L. (author), Mulder, P. (author), van der Hoorn, J.W.A. (author), Verheij, J. (author), van Dam, A.D. (author), Boon, M.R. (author), Princen, H.M.G. (author), Havekes, L.M. (author), Kleemann, R. (author), van den Hoek, A.M. (author)

BACKGROUND AND PURPOSE: Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested...

article 2015

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Low-grade inflammation, diet composition and health: Current research evidence and its translation

Minihane, A.M. (author), Vinoy, S. (author), Russell, W.R. (author), Baka, A. (author), Roche, H.M. (author), Tuohy, K.M. (author), Teeling, J.L. (author), Blaak, E.E. (author), Fenech, M. (author), Vauzour, D. (author), McArdle, H.J. (author), Kremer, B.H.A. (author), Sterkman, L. (author), Vafeiadou, K. (author), Benedetti, M.M. (author), Williams, C.M. (author), Calder, P.C. (author)

The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's...

article 2015

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Role of metabolic overload and metabolic inflammation in the development of Nonalcoholic Steatohepatitis (NASH)

Liang, W. (author)

Overload of nutrients can lead to diet-induced inflammation, also called metabolic inflammation, which is thought to play an important role in many metabolic diseases, including the development of nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of pathologies that range from simple hepatic steatosis to nonalcoholic...

doctoral thesis 2015

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Role of Macrophage Migration Inhibitory Factor in Obesity, Insulin Resistance, Type 2 Diabetes, and Associated Hepatic Co-Morbidities: A Comprehensive Review of Human and Rodent Studies

Morrison, M.C. (author), Kleemann, R. (author)

Obesity is associated with a chronic low-grade inflammatory state that drives the -development of obesity-related co-morbidities such as insulin resistance/type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. This metabolic inflammation is thought to originate in the adipose tissue, which becomes inflamed and...

article 2015

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Replacement of Dietary Saturated Fat by PUFA-Rich Pumpkin Seed Oil Attenuates Non-Alcoholic Fatty Liver Disease and Atherosclerosis Development, with Additional Health Effects of Virgin over Refined Oil

Mulder, P. (author), Stavro, P.M. (author), Manuel Suárez, M. (author), Arola-Arnal, A. (author), van Duyvenvoorde, W. (author), Kooistra, T. (author), Wielinga, P.Y. (author), Kleemann, R. (author)

Background and Aims As dietary saturated fatty acids are associated with metabolic and cardiovascular disease, a potentially interesting strategy to reduce disease risk is modification of the quality of fat consumed. Vegetable oils represent an attractive target for intervention, as they largely determine the intake of dietary fats. Furthermore,...

article 2015

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Toxicogenomics directory of chemically exposed human hepatocytes

Grinberg, M. (author), Stöber, R.M. (author), Edlund, K. (author), Rempel, E. (author), Godoy, P. (author), Reif, R. (author), Widera, A. (author), Madjar, K. (author), Schmidt-Heck, W. (author), Marchan, R. (author), Sachinidis, A. (author), Spitkovsky, D. (author), Hescheler, J. (author), Carmo, H. (author), Arbo, M.D. (author), van de Water, B. (author), Wink, S. (author), Vinken, M. (author), Rogiers, V. (author), Escher, S. (author), Hardy, B. (author), Mitic, D. (author), Myatt, G. (author), Waldmann, T. (author), Mardinoglu, A. (author), Damm, G. (author), Seehofer, D. (author), Nüssler, A. (author), Weiss, T.S. (author), Oberemm, A. (author), Lampen, A. (author), Schaap, M.M. (author), Luijten, M. (author), van Steeg, H. (author), Thasler, W.E. (author), Kleinjans, J.C.S. (author), Stierum, R.H. (author), Leist, M. (author), Rahnenführer, J. (author), Hengstler, J.G. (author)

A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge...

article 2014

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Inhibition of the central melanocortin system decreases brown adipose tissue activity

Kooijman, S. (author), Boon, M.R. (author), Parlevliet, E.T. (author), Geerling, J.J. (author), van de Pol, V. (author), Romijn, J.A. (author), Havekes, L.M. (author), Meurs, I. (author), Rensen, P.C.N. (author)

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE∗3...

article 2014