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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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Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

Martínez-Arranz, I. (author), Bruzzone, C. (author), Noureddin, M. (author), Gil-Redondo, R. (author), Mincholé, I. (author), Bizkarguenaga, M. (author), Arretxe, E. (author), Iruarrizaga-Lejarreta, M. (author), Fernández-Ramos, D. (author), Lopitz-Otsoa, F. (author), Mayo, R. (author), Embade, N. (author), Newberry, E. (author), Mittendorf, B. (author), Izquierdo-Sánchez, L. (author), Smid, V. (author), Arnold, J. (author), Iruzubieta, P. (author), Pérez Castaño, Y. (author), Krawczyk, M. (author), Marigorta, U.M. (author), Morrison, M.C. (author), Kleemann, R. (author), Martín-Duce, A. (author), Hayardeny, L. (author), Vitek, L. (author), Bruha, R. (author), Aller de la Fuente, R. (author), Crespo, J. (author), Romero-Gomez, M. (author), Banales, J.M. (author), Arrese, M. (author), Cusi, K. (author), Bugianesi, E. (author), Klein, S. (author), Lu, S.C. (author), Anstee, Q.M. (author), Millet, O. (author), Davidson, N.O. (author), Alonso, C. (author), Mato, J.M. (author)

Background and Aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and Results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD...

article 2022

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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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High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr-/-.Leiden mouse model

Komninos, D. (author), Ramos, L. (author), van der Heijden, G.W. (author), Morrison, M.C. (author), Kleemann, R. (author), van Herwaarden, A.E. (author), Kiliaan, A.J. (author), Arnoldussen, I.A.C. (author)

Obesity can disturb spermatogenesis and subsequently affect male fertility and reproduction. In our study, we aim to elucidate at which cellular level of adult spermatogenesis the detrimental effects of obesity manifest. We induced high fat diet (HFD) obesity in low-density lipoprotein receptor knock-out Leiden (Ldlr−/−.Leiden) mice, and studied...

article 2022

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Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr−/−.Leiden mice

Arnoldussen, I.A.C. (author), Morrison, M.C. (author), Wiesmann, M. (author), van Diepen, J.A. (author), Worms, N. (author), Voskuilen, M. (author), Verweij, V. (author), Greenen, B. (author), Pujol Gauldo, N. (author), van der Logt, L. (author), Gross, G. (author), Verschuren, L. (author), Kleemann, R. (author), Kiliaan, A.J. (author)

Background. Milk-fat globule membrane (MFGM) is a complex structure secreted by the mammary gland and present in mammalian milk. MFGM contains lipids and glycoproteins as well as gangliosides, which may be involved in myelination processes. Notably, myelination and thereby white matter integrity are often altered in obesity. Furthermore, MFGM...

article 2022

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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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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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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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Short‐term LPS induces Aortic Valve thickening in ApoE*3Leiden mice

van Broekhoven, A. (author), Krijnen, P.A.J. (author), Fuijkschot, W.W. (author), Morrison, M.C. (author), Zethof, I.P.A. (author), van Wieringen, W.N. (author), Smulders, Y.M. (author), Niessen, H.W.M. (author), Vonk, A.B.A. (author)

Background Recently, it was shown that 12 weeks of lipopolysacharide (LPS) administration to non‐atherosclerotic mice induced thickening of the aortic heart valve (AV). Whether such effects may also occur even earlier is unknown. As most patients with AV stenosis also have atherosclerosis, we studied the short‐term effect of LPS on the AVs in an...

article 2019

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Sex-Specific Differences in Fat Storage, Development of Non-Alcoholic Fatty Liver Disease and Brain Structure in Juvenile HFD-Induced Obese Ldlr-/-.Leiden Mice

Jacobs, S.A.H. (author), Gart, E. (author), Vreeken, D. (author), Franx, B.A.A. (author), Wekking, L. (author), Verweij, V.G.M. (author), Worms, N. (author), Schoemaker, M.H. (author), Gross, G. (author), Morrison, M.C. (author), Kleemann, R. (author), Arnoldussen, I.A.C. (author), Kiliaan, A.J. (author)

Background: Sex-specific differences play a role in metabolism, fat storage in adipose tissue, and brain structure. At juvenile age, brain function is susceptible to the effects of obesity; little is known about sex-specific differences in juvenile obesity. Therefore, this study examined sex-specific differences in adipose tissue and liver of...

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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Variable cartilage degradation in mice with diet-induced metabolic dysfunction: Food for thought

Kozijn, A.E. (author), Gierman, L.M. (author), van der Ham, F. (author), Mulder, P. (author), Morrison, M.C. (author), Kühnast, S. (author), van der Heijden, R.A. (author), Stavro, P.M. (author), van Koppen, A. (author), Pieterman, E.J. (author), van den Hoek, A.M. (author), Kleemann, R. (author), Princen, H.M.G. (author), Mastbergen, S.C. (author), Lafeber, F.P.J.G. (author), Zuurmond, A.M. (author), Bobeldijk, I. (author), Weinans, H. (author), Stoop, R. (author)

Objective. Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was...

article 2018

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LPS-Induced Systemic Inflammation Does Not Alter Atherosclerotic Plaque Area or Inflammation in APOE3*LEIDEN Mice in the Early Phase Up to 15 Days

Fuijkschot, W.W. (author), Morrison, M.C. (author), Zethof, I.P.A. (author), Krijnen, P.A.J. (author), Kleemann, R. (author), Niessen, H.W.M. (author), Smulders, Y.M. (author)

Background and Aims: Observational studies show a peak incidence in cardiovascular events during and early after clinical conditions associated with substantial systemic inflammation, such as pneumonia. The acuteness of this increased risk suggests rapid plaque destabilization and associated intraplaque inflammation. We evaluated whether...

article 2018

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StemBell therapy stabilizes atherosclerotic plaques after myocardial infarction

Woudstra, L. (author), Meinster, E. (author), van Haren, L. (author), Kay, A.M. (author), Kooman, M. (author), Belien, J.A.M. (author), Morrison, M.C. (author), van Rossum, A.C. (author), Helder, M.N. (author), Juffermans, J.M. (author), Niessen, H.W.M. (author), Krijnen, P.A.J. (author)

Background aims. After a myocardial infarction (MI) atherosclerosis is accelerated leading to destabilization of the atherosclerotic plaque. mesenchymal stromal cells are a promising therapeutic option for atherosclerosis. Previously, we demonstrated a novel stem cell delivery technique, with adipose stem cells coupled to microbubbles (i.e.,...

article 2018

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Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr-/-.Leiden Mice

Morrison, M.C. (author), Verschuren, L. (author), Salic, K. (author), Verhij, J. (author), Menke, A. (author), Wielinga, P.Y. (author), Iruarrizaga-Lejarretts, M. (author), Gole, L. (author), Yu, W.M. (author), Turner, S. (author), Caspers, M.P.M. (author), Martinez-Arranz, I. (author), Pieterman, E. (author), Stoop, R. (author), van Koppen, A. (author), van den Hoek, A.M. (author), Mato, J.M. (author), Hanemaaijer, R. (author), Alonso, C. (author), Kleemann, R. (author)

Concerns have been raised about whether preclinical models sufficiently mimic molecular disease processes observed in nonalcoholic steatohepatitis (NASH) patients, bringing into question their translational value in studies of therapeutic interventions in the process of NASH/fibrosis. We investigated the representation of molecular disease...

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