Wim van Duyvenvoorde

Netherlands Organisation for Applied Scientific Research

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Robert Kleemann

Netherlands Organisation for Applied Scientific Research

P. Hans

Netherlands Organisation for Applied Scientific Research

Martine C. Morrison

Netherlands Organisation for Applied Scientific Research

Eveline Gart

Netherlands Organisation for Applied Scientific Research

Lars Verschuren

Netherlands Organisation for Applied Scientific Research

Aswin Menke

Netherlands Organisation for Applied Scientific Research

Martien Caspers

Netherlands Organisation for Applied Scientific Research

Kanita Salic

Netherlands Organisation for Applied Scientific Research

Louis M. Havekes

Leiden University Medical Center

Jaap Keijer

Wageningen University & Research

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Netherlands Organisation for Applied Scientific Research

Leiden University Medical Center

Radboud University Nijmegen

Radboud University Medical Center

Leiden University

University of Amsterdam

University Medical Center

Utrecht University

Academic Medical Center

Wageningen University & Research

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

International Journal of Obesity (2015)

Petra Mulder Martine C. Morrison Peter Y. Wielinga Wim van Duyvenvoorde T. Kooistra

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. A time-course study in C57BL/6J mice was performed to establish which WAT depot is most susceptible to develop inflammation during high-fat diet (HFD)-induced obesity. Crown-like structures (CLS) were quantified in epididymal (eWAT), mesenteric (mWAT) and inguinal/subcutaneous (iWAT) WAT. The contribution of inflamed WAT to NAFLD progression was investigated by surgical removal of a selected WAT depot and compared with sham surgery. Plasma markers were analyzed by enzyme-linked immunosorbent assay (cytokines/adipokines) and lipidomics (lipids). In eWAT, CLS were formed already after 12 weeks of HFD, which coincided with maximal adipocyte size and fat depot mass, and preceded establishment of non-alcoholic steatohepatitis (NASH). By contrast, the number of CLS were low in mWAT and iWAT. Removal of inflamed eWAT after 12 weeks (eWATx group), followed by another 12 weeks of HFD feeding, resulted in significantly reduced NASH in eWATx. Inflammatory cell aggregates (−40%; P<0.05) and inflammatory genes (e.g., TNFα, −37%; P<0.05) were attenuated in livers of eWATx mice, whereas steatosis was not affected. Concomitantly, plasma concentrations of circulating proinflammatory mediators, viz. leptin and specific saturated and monounsaturated fatty acids, were also reduced in the eWATx group. Intervention in NAFLD progression by removal of inflamed eWAT attenuates the development of NASH and reduces plasma levels of specific inflammatory mediators (cytokines and lipids). These data support the hypothesis that eWAT is causally involved in the pathogenesis of NASH.

Steatohepatitis

Proinflammatory cytokine

Steatosis

10.1038/ijo.2015.226

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Citations (85)

A Dietary Mixture Containing Fish Oil, Resveratrol, Lycopene, Catechins, and Vitamins E and C Reduces Atherosclerosis in Transgenic Mice1–3

Journal of Nutrition (2011)

Lars Verschuren Peter Y. Wielinga Wim van Duyvenvoorde Samira Tijani Karin Toet

10.3945/jn.110.133751

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Citations (43)

Liver-associated dysmetabolism is related to brain structure and perfusion changes in obesity: the BARICO study

Journal of Hepatology (2023)

Florine Seidel Debby Vreeken Emma Custers Maximilian Wiesmann Serdar Özsezen

10.1016/s0168-8278(23)02179-7

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Propionic acid intervention in obese LDLR

Eveline Gart Anouk C. Tengeler Maximilian Wiesmann Ilse A.C. Arnoldussen Wim van Duyvenvoorde

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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

PLoS ONE (2015)

Martine C. Morrison Petra Mulder P. Mark Stavro Manuel Suárez Anna Arola‐Arnal

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, besides potential health effects conferred by the type of fatty acids in a vegetable oil, other minor components (e.g. phytochemicals) may also have health benefits. Here, we investigated the potential long-term health effects of isocaloric substitution of dietary fat (i.e. partial replacement of saturated by unsaturated fats), as well as putative additional effects of phytochemicals present in unrefined (virgin) oil on development of non-alcoholic fatty liver disease (NAFLD) and associated atherosclerosis. For this, we used pumpkin seed oil, because it is high in unsaturated fatty acids and a rich source of phytochemicals. Methods ApoE*3Leiden mice were fed a Western-type diet (CON) containing cocoa butter (15% w/w) and cholesterol (1% w/w) for 20 weeks to induce risk factors and disease endpoints. In separate groups, cocoa butter was replaced by refined (REF) or virgin (VIR) pumpkin seed oil (comparable in fatty acid composition, but different in phytochemical content). Results Both oils improved dyslipidaemia, with decreased (V)LDL-cholesterol and triglyceride levels in comparison with CON, and additional cholesterol-lowering effects of VIR over REF. While REF did not affect plasma inflammatory markers, VIR reduced circulating serum amyloid A and soluble vascular adhesion molecule-1. NAFLD and atherosclerosis development was modestly reduced in REF, and VIR strongly decreased liver steatosis and inflammation as well as atherosclerotic lesion area and severity. Conclusions Overall, we show that an isocaloric switch from a diet rich in saturated fat to a diet rich in unsaturated fat can attenuate NAFLD and atherosclerosis development. Phytochemical-rich virgin pumpkin seed oil exerts additional anti-inflammatory effects resulting in more pronounced health effects.

10.1371/journal.pone.0139196

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

International Journal of Molecular Sciences (2019)

Kanita Salic Eveline Gart Florine Seidel Lars Verschuren Martien Caspers

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 with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr -/-.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4%

Steatosis

10.3390/ijms20184359

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Citations (41)

Combined Analysis of Pharmacokinetic and Efficacy Data of Preclinical Studies with Statins Markedly Improves Translation of Drug Efficacy to Human Trials

Journal of Pharmacology and Experimental Therapeutics (2013)

Evita van de Steeg Robert Kleemann Harm T. Jansen Wim van Duyvenvoorde Erik H. Offerman

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) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein ≥ 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R² = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R² = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models.

Lovastatin

Pitavastatin

Efficacy

10.1124/jpet.113.208595

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Citations (28)

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

Journal of Hepatology (2023)

Eveline Gart Wim van Duyvenvoorde Jessica Snabel Christa de Ruiter Joline Attema

Dynamics

10.1016/s0168-8278(23)02222-5

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Dietary supplementation with vitamin E to protect LDL from lipid peroxidation

Atherosclerosis (1994)

P. Hans Wim van Duyvenvoorde R. Buytenhek Arnoud van der Laarse G. van Poppel

10.1016/0021-9150(94)93224-7

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Effect of 17β-Estradiol on Plasma Lipids and LDL Oxidation in Postmenopausal Women With Type II Diabetes Mellitus

Arteriosclerosis Thrombosis and Vascular Biology (1997)

H. E. Brussaard J.A. Gevers Leuven Cornelis Kluft H. Michiel J. Krans Wim van Duyvenvoorde

In type II diabetes mellitus the altered hormonal state after menopause may represent an additional cardiovascular risk factor. Estrogen replacement therapy (ERT) is associated with a decreased cardiovascular risk, at least in nondiabetic postmenopausal women. We studied the effect of ERT on plasma lipids and lipoproteins and on LDL oxidation in 40 postmenopausal women with type II diabetes but with minimal vascular complications in a randomized placebo-controlled trial. Twenty patients were treated orally with 2 mg/d micronized 17β-estradiol and 20 patients with placebo for 6 weeks. Plasma total cholesterol (−6%, P =.04), LDL cholesterol (−16%, P =.0001), and apoB (−11%, P =.001) levels decreased and HDL cholesterol (20%, P =.0001) and apoA-I (14%, P =.0001) levels increased after ERT compared with placebo. Glycated hemoglobin (HbA1c) decreased significantly after ERT (−3%, P =.03), the cholesterol content of the LDL particles decreased (−5%, P =.006), triglyceride content increased (16%, P =.01), and LDL particle size did not change significantly. ERT had no effect on parameters of LDL oxidation. We conclude that plasma levels of HDL cholesterol, apoA-I, LDL cholesterol, apoB, and glycated hemoglobin are improved in postmenopausal women with type II diabetes mellitus after treatment with 17β-estradiol, indicative of a better metabolic control, and that ERT has no effect on LDL oxidizability.

Glycated hemoglobin

10.1161/01.atv.17.2.324

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Citations (74)