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Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr-/-.Leiden mice

Gart, E. (author), van Duyvenvoorde, W. (author), Snabel, J. (author), de Ruiter, C. (author), Attema, J. (author), Caspers, M.P.M. (author), Lek, S. (author), van Heuven, B.J. (author), Speksnijder, A.G.C.L. (author), Giera, M. (author), Menke, A. (author), Salic, K. (author), Bence, K.K. (author), Tesz, G.J. (author), Keijzer, J. (author), Kleemann, R. (author), Morrison, M.C. (author)

Background: NAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood. Methods: High-fat-diet (HFD)-fed Ldlr-/-...

article 2023

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Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice

Seidel, F. (author), Kleemann, R. (author), van Duyvenvoorde, W. (author), van Trigt, N. (author), Keijzer, N. (author), van der Kooij, S. (author), van Kooten, C. (author), Verschuren, L. (author), Menke, A. (author), Kiliaan, A.J. (author), Winter, J. (author), Hughes, T.R. (author), Morgan, P. (author), Baas, F. (author), Fluiter, K. (author), Morrison, M.C. (author)

Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains...

article 2022

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Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr-/-.Leiden mice with manifest obesity-associated NASH

Gart, E. (author), van Duyvenvoorde, W. (author), Caspers, M.P.M. (author), van Trigt, N. (author), Snabel, J. (author), Menke, A. (author), Keijer, J. (author), Salic, K. (author), Morrison, M.C. (author), Kleemann, R. (author)

Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative...

article 2022

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Heat-Inactivated Akkermansia muciniphila Improves Gut Permeability but Does Not Prevent Development of Non-Alcoholic Steatohepatitis in Diet-Induced Obese Ldlr-/-.Leiden Mice

Morrison, M.C. (author), Gart, E. (author), van Duyvenvoorde, W. (author), Snabel, J. (author), Nielsen, M.J. (author), Leeming, D.J. (author), Menke, A. (author), Kleemann, R. (author)

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host metabolism, both when...

article 2022

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Lipid ratios representing SCD1, FADS1, and FADS2 activities as candidate biomarkers of early growth and adiposity

Olga, L. (author), van Diepen, J.A. (author), Bobeldijk-Pastorova, I. (author), Gross, G. (author), Prentice, S.M. (author), Snowden, S.G. (author), Furse, S. (author), Kooistra, T. (author), Hughes, I.A. (author), Schoemaker, M.H. (author), van Tol, E.A.F. (author), van Duyvenvoorde, W. (author), Wielinga, P.Y. (author), Ong, K.K. (author), Dunger, D.B. (author), Kleemann, R. (author), Koulman, A. (author)

Background: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort. Methods:...

article 2021

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Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine

Mueller, A.M. (author), Kleemann, R. (author), Gart, E. (author), van Duyvenvoorde, W. (author), Verschuren, L. (author), Caspers, M. (author), Menke, A. (author), Krömmelbein, N. (author), Salic, K. (author), Burmeister, Y. (author), Seilheimer, B. (author), Morrison, M.C. (author)

Background: Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in...

article 2021

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Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

Gart, E. (author), van Duyvenvoorde, W. (author), Toet, K. (author), Caspers, M.P.M. (author), Verschuren, L. (author), Nielsen, M.J. (author), Leeming, D.J. (author), Lima, E.S. (author), Menke, A. (author), Hanemaaijer, R. (author), Keijer, J. (author), Salic, K. (author), Kleemann, R. (author), Morrison, M.C. (author)

In obesity-associated non-alcoholic steatohepatitis (NASH), persistent hepatocellular damage and inflammation are key drivers of fibrosis, which is the main determinant of NASH-associated mortality. The short-chain fatty acid butyrate can exert metabolic improvements and anti-inflammatory activities in NASH. However, its effects on NASH...

article 2021

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Krill Oil Treatment Increases Distinct PUFAs and Oxylipins in Adipose Tissue and Liver and Attenuates Obesity-Associated Inflammation via Direct and Indirect Mechanisms

Gart, E. (author), Salic, K. (author), Morrison, M.C. (author), Caspers, M. (author), van Duyvenvoorde, W. (author), Heijnk, M. (author), Giera, M. (author), Bobeldijk-Pastorova, I. (author), Keijer, J. (author), Storsve, A.B. (author), Hals, P.A. (author), Kleemann, R. (author)

The development of obesity is characterized by the metabolic overload of tissues and subsequent organ inflammation. The health effects of krill oil (KrO) on obesity-associated inflammation remain largely elusive, because long-term treatments with KrO have not been performed to date. Therefore, we examined the putative health effects of 28 weeks...

article 2021

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Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr-/-.Leiden mice

Tengeler, A.C. (author), Gart, E. (author), Wiesmann, M. (author), Arnoldussen, I.A.C. (author), Verschuren, L. (author), van Duyvenvoorde, W. (author), Hoogstad, M. (author), Dederen, P.J. (author), Verweij, V. (author), Geenen, B. (author), Kozicz, T. (author), Kleemann, R. (author), Morrison, M.C. (author), Kiliaan, A.J. (author)

The obesity epidemic increases the interest to elucidate impact of short‐chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity...

article 2020

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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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Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice

Arnoldussen, I.A.C. (author), Wiesmann, M. (author), Pelgrim, C.E. (author), Wielemaker, E.M. (author), van Duyvenvoorde, W. (author), Amaral-Santos, P.L. (author), Verschuren, L. (author), Keijser, B.J.F. (author), Heerschap, A. (author), Kleemann, R. (author), Wielinga, P.Y. (author), Kiliaan, A.J. (author)

Objective: Midlife obesity affects cognition and increases risk of developing dementia. Recent data suggest that intake of the short chain fatty acid butyrate could improve memory function, and may protect against diet-induced obesity by reducing body weight and adiposity. Subjects: We examined the impact of a high-fat diet (HFD) followed by...

article 2017

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Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis in LDLR-/-.Leiden mice

Morrison, M.C. (author), Mulder, P. (author), Salic, K. (author), Verheij, J. (author), Liang, W. (author), van Duyvenvoorde, W. (author), Menke, A. (author), Kooistra, T. (author), Kleemann, R. (author), Wielinga, P.Y. (author)

Background/objectives: Non-alcoholic steatohepatitis (NASH) is a serious liver condition, closely associated with obesity and insulin resistance. Recent studies have suggested an important role for inflammasome/caspase-1 in the development of NASH, but the potential therapeutic value of caspase-1 inhibition remains unclear. Therefore, we aimed...

article 2016

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Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity

Mulder, P. (author), Morrison, M.C. (author), Wielinga, P.Y. (author), van Duyvenvoorde, W. (author), Kooistra, T. (author), Kleemann, R. (author)

Background: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with abdominal obesity. Growing evidence suggests that inflammation in specific depots of white adipose tissue (WAT) has a key role in NAFLD progression, but experimental evidence for a causal role of WAT is lacking. Methods: A time-course study in C57BL/6J mice was...

article 2016

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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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Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trialss

van de Steeg, E. (author), Kleemann, R. (author), Jansen, H.T. (author), van Duyvenvoorde, W. (author), Offerman, E.H. (author), Wortelboer, H.M. (author), DeGroot, J. (author)

Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) trans-genic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining...

article 2013

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Effects of probiotic Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS supplementation on intestinal and systemic markers of inflammation in ApoE*3Leiden mice consuming a high-fat diet

Oksaharju, A. (author), Kooistra, T. (author), Kleemann, R. (author), van Duyvenvoorde, W. (author), Miettinen, M. (author), Lappalainen, J. (author), Lindstedt, K.A. (author), Kovanen, P.T. (author), Korpela, R. (author), Kekkonen, R.A. (author)

A high-fat diet disturbs the composition and function of the gut microbiota and generates local gut-associated and also systemic responses. Intestinal mast cells, for their part, secrete mediators which play a role in the orchestration of physiological and immunological functions of the intestine. Probiotic bacteria, again, help to maintain the...

article 2013

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Differential Effects of Drug Interventions and Dietary Lifestyle in Developing Type 2 Diabetes and Complications: A Systems Biology Analysis in LDLr-/- Mice

Radonjic, M. (author), Wielinga, P.Y. (author), Wopereis, S. (author), Kelder, T. (author), Goelela, V.S. (author), Verschuren, L. (author), Toet, K. (author), van Duyvenvoorde, W. (author), van der Werff van der Vat, B. (author), Stroeve, J.H.M. (author), Cnubben, N. (author), Kooistra, T. (author), van Ommen, B. (author), Kleemann, R. (author)

Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM). Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of...

article 2013

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Identification of prognostic and diagnostic biomarkers of glucose intolerance in ApoE3Leiden mice

Wopereis, S. (author), Radonjic, M. (author), Rubingh, C. (author), van Erk, M. (author), Smilde, A. (author), van Duyvenvoorde, W. (author), Cnubben, N. (author), Kooistra, T. (author), van Ommen, B. (author), Kleemann, R. (author)

The prevalence of diabetes mellitus Type 2 could be significantly reduced by early identification of subjects at risk, allowing for better prevention and earlier treatment. Glucose intolerance (GI) is a hallmark of the prediabetic stage. This study aims at identifying 1) prognostic biomarkers predicting the risk of developing GI later in life...

article 2012

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A dietary mixture containing fish oil, resveratrol, lycopene, catechins, and vitamins E and C reduces atherosclerosis in transgenic mice

Verschuren, L. (author), Wielinga, P.Y. (author), van Duyvenvoorde, W. (author), Tijani, S. (author), Toet, K. (author), van Ommen, B. (author), Kooistra, T. (author), Kleemann, R. (author)

Chronic inflammation and proatherogenic lipids are important risk factors of cardiovascular disease (CVD). Specific dietary constituents such as polyphenols and fish oils may improve cardiovascular risk factors and may have a beneficial effect on disease outcomes. We hypothesized that the intake of an antiinflammatory dietary mixture (AIDM)...

article 2011

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Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis

Nieuwenhuizen, W.F. (author), Duivenvoorden, I. (author), Voshol, P.J. (author), Rensen, P.C.N. (author), van Duyvenvoorde, W. (author), Romijn, J.A. (author), Emeis, J.J. (author), Havekes, L.M. (author), TNO Kwaliteit van Leven (author)

The prevalence of dyslipidemia and obesity resulting from excess energy intake and physical inactivity is increasing. The liver plays a pivotal role in the systemic lipid homeostasis. Effective, natural dietary interventions that lower plasma lipids and promote liver health are needed. APOE*3Leiden mice were fed a Western-type diet, supplemented...

article 2007