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Prof. PhD W.H. Lamers

Position
Full Professor
Main activities
Education, Research
Specialisation
Anatomy, Molecular biology, Nutrition, Liver
Focus of research

Proteins turn over continuously. Protein breakdown generates toxic ammonia. Glutamine and urea synthesis are the main pathways for ammonia detoxification, but their mutual dependence is still not sorted out. A ~5% reduction in urea synthesis causes lethal hyperammonemia, but a 35% reduction in glutamine synthesis produces no phenotype, even though glutamine synthetase is, thus far, held responsible for preventing hyperammonemia. Using tissue-specific knockout mice and stable isotope-based fluxomics, we investigate the interorgan dependence and (patho )physiological determinants of glutamine and urea synthesis, and the requirement of glutamine synthesis for urea synthesis. Environmental conditions that are studied include high-protein diets (high-protein diets are satiating and facilitate weight reduction), fasting (a proxy for cachexia), and intestinal bacterial overgrowth and acidosis (the encephalopathy-provoking condition in cirrhotic patients).

The pelvic floor is the last underexplored area in human anatomy, even though it plays a key role in deliveries and accounts for incontinence in one-third of our female postmenopausal population. Because classical dissection has proven an inadequate research tool and the correspondence between radiological and anatomical details remains largely incomplete in this region, we employ ultra-large sections and immunohistochemistry of fetal and adult specimens as tools to assemble annotated three-dimensional maps of the pelvic floor.

 

Key publications
  • He Youji, Hakvoort Theodorus B. M., Vermeulen Jacqueline L. M., Labruyère Wilhelmina T., de Waart D. Rudi, van der Hel W. Saskia, Ruijter Jan M., Uylings Harry B. M., Lamers Wouter H. Glutamine Synthetase Deficiency in Murine Astrocytes Results in Neonatal Death Glia 2010;58 (6):741-754 [PubMed]
  • He Youji, Hakvoort Theodorus B. M., Köhler S. Eleonore, Vermeulen Jacqueline L. M., de Waart D. Rudi, de Theije Chiel, ten Have Gabrie A. M., van Eijk Hans M. H., Kunne Cindy, Labruyere Wilhelmina T., Houten Sander M., Sokolovic Milka, Ruijter Jan M., Deutz Nicolaas E. P., Lamers Wouter H. Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification Journal of biological chemistry 2010;285 (13):9516-9524 [PubMed]
  • Stanulović Vesna S., Kyrmizi Irene, Kruithof-de Julio Marianna, Hoogenkamp Maarten, Vermeulen Jacqueline L. M., Ruijter Jan M., Talianidis Iannis, Hakvoort Theodorus B. M., Lamers Wouter H. Hepatic HNF4alpha deficiency induces periportal expression of glutamine synthetase and other pericentral enzymes Hepatology (Baltimore, Md.) 2007;45 (2):433-444 [PubMed]
  • Wallner Christian, Dabhoiwala Noshir F., Deruiter Marco C., Lamers Wouter H. The anatomical components of urinary continence European urology 2009;55 (4):932-943 [PubMed]
  • Wallner Christian, van Wissen Julia, Maas Cornelis P., Dabhoiwala Noshir F., Deruiter Marco C., Lamers Wouter H. The contribution of the levator ani nerve and the pudendal nerve to the innervation of the levator ani muscles; a study in human fetuses European urology 2008;54 (5):1136-1142 [PubMed]
All Publications
Research programmes

Prof. PhD W.H. Lamers (Structure-function relations in the liver)

Fasting does not change the tissue composition of liver and intestine qualitatively. In the intestine, fasting reduces cell turnover and induces a biphasic metabolic response that first facilitates lactate and ketone-body, and then glucose and ketone-body synthesis. In the liver, the adaptive response is monophasic and facilitates gluconeogenesis and ketone-body synthesis. Presently, we investigate the response to fasting in additional organs to interorgan coordination between intestine, liver, muscle, kidney, and brain.

Our ongoing studies on transcriptional regulation of liver-specific gene expression revealed that the periportal expression of the pericentral enzyme glutamine synthetase (GS) is suppressed by the transcription factor HNF4a. Furthermore, we showed that the regulation of expression of the periportal enzyme carbamoylphosphate synthetase by the transcription factor PPARa depends on the hormonal occupancy of the glucocorticoid receptor. Finally, we began to identify proteins in purified periportal and pericentral hepatocyte nuclei from “Pck-GFP” and “GS-GFP” mice.

The amino acid glutamine is a crucial transport vehicle for toxic ammonia. The complete elimination of the GS gene in mice causes death in early embryos, while inactivation in the brain causes death 2 days after birth. However, inactivation of GS in liver and/or muscle does not entail a phenotype, unless the animals are fasted or fed a high-protein diet. Apparently, many putative crucial functions only become visible under a functional challenge.

In a pilot experiment, we showed that a high-protein diet prevents liver steatosis and inflammation, suggesting that nutrition can cure inflamed fatty livers. As animal model for fatty-liver disease, mice are continuously overfed via a gastrostomy tube. These mice become obese, insulin-resistant and diabetic, and develop steatohepatitis.


Themes: Gastro-intestinal Diseases and Metabolic Disorders

This research group participates in the Amsterdam Center for Metabolism