Effekt einer oralen Supplementation von Arginin, Citrullin und Glutamin auf die Entstehung und das Voranschreiten der nicht-alkoholbedingten Fettlebererkrankungen (NAFLD): Rolle von Geschlecht und Alter

• Antragstellerin: Professorin Dr. Ina Bergheim
• Fachliche Zuordnung: Ernährungswissenschaften ; Gastroenterologie
• Förderung: Förderung von 2010 bis 2020
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 183849079

• Erstellungsjahr: 2021

Zusammenfassung der Projektergebnisse

Non-alcoholic fatty liver disease (NAFLD) is by now the most common liver disease worldwide. In the last decades several risk factors for the development of NAFLD have been identified among which a general overnutrition but also dietary composition (e.g. a diet rich in saturated fatty acids and fructose) seem to be of key importance. It further has been suggested that alterations of intestinal microbiota composition and intestinal barrier function may also be critical in the development of NAFLD. However, molecular mechanisms have not yet been fully understood. The supplementation of amino acids like arginine, citrulline and glutamine has been indicated to have protective effects on intestinal barrier and the development of liver disease of various etiologies. Starting from this background, the aim of the first funding period which was initiated in response to a call of the ANR and DFG for German-French collaborative projects under the general topic of “nutrition research“ was to determine if arginine, citrulline and glutamine protects rodents from the development of fructose-induced NAFLD and to determine underlying molecular mechanisms. Key findings of the first funding period included that all three amino acids protected mice from the development of diet-induced early stages of NAFLD e.g., the development of steatosis and early inflammatory alterations. Results of these studies also suggested that the protective effects of both arginine and citrulline were related to effects on intestinal barrier function while the protective effects of glutamine seemed to stem predominantly from its effects on the liver. Accordingly, the main aim of the second funding period was to further delineate molecular mechanism underlying the protective effects of the different amino acids and to determine if effects alike are also found when NAFLD already has developed. Indeed, supplementation of all three amino acids attenuated the progression of a pre-existing NAFLD to later stages of the disease being associated even with an improvement of the disease; however, not to the level of controls. Results of our studies further suggest that the oral supplementation of both arginine and citrulline at least in large parts exert their protective and curative effects through altering NO-homeostasis in small intestinal tissue. And while the supplementation of glutamine also had protective effects on the development and progression of NAFLD further studies are still at need to determine underlying molecular mechanisms.

Projektbezogene Publikationen (Auswahl)

• “Protective effect of glutamine on the development of a Western style diet-induced non-alcoholic steatohepatitis (NASH) in mice”, November 2013, AASLD, Washington DC, USA, Hepatology, 2013, Volume 58, Issue S1, page 177A
  Sellmann C, Jin C, De Bandt J-P, Bergheim I
  
• “Einfluss von Arginin und Citrullin auf die Entstehung einer Western Style Diät-induzierten nicht-alkoholbedingten Fettlebererkrankung (NAFLD): Untersuchungen im Mausmodell”, June 2014, DGEM, Ludwigsburg, Germany (1st place poster award)
  Sellmann C, Degen C, Jin C, Engstler J, De Bandt J-P, Bergheim I
  
• “Protective effect of an oral glutamine supplementation on the development of a Western style diet-induced non-alcoholic steatohepatitis (NASH) in mice”, March 2014, DGE, Paderborn, Germany
  Sellmann C, Jin C, Engstler J, De Bandt J-P, Bergheim I
  
• Oral glutamine supplementation protects female mice from nonalcoholic steatohepatitis. J Nutr. 2015 Oct;145(10):2280-6
  Sellmann C, Jin CJ, Degen C, De Bandt J-P, Bergheim I
  
• Glutamin: Neuer Ansatz in der Therapie der nicht-alkoholbedingten Fettlebererkrankung (NAFLD)?, Nutrition News Nr. 3 2017
  Baumann A, Bergheim I
  
• Oral arginine supplementation protects female mice from the onset of nonalcoholic steatohepatitis. Amino Acid. 2017 Jul;19(7):1215-1225
  Sellmann C, Degen C, Jin CJ, Nier A, Engstler AJ, Hasan Alkhatib D, De Bandt J-P, Bergheim I
  
• Oral citrulline supplementation protects female mice from the development of non-alcoholic fatty liver disease (NAFLD). Eur J Nutr. 2017 Dec;56(8):2519-2527
  Sellmann C, Jin CJ, Engstler AJ, De Bandt J-P, Bergheim I
  
• Oral supplementation of citrulline in the therapy of a diet-induced non-alcoholic steatohepatitis (NASH): Role of intestinal microbiota and barrier function, Seeon Conference – Microbiota, Probiotics and Host 2017, Seeon, Germany
  Baumann A, Camarinha-Silva A, Sellmann C, Brandt A, Engstler AJ, Jin, CJ, Rajcic D, Bergheim I
  
• Oral supplementation of glutamine attenuates the progression of nonalcoholic steatohepatitis in C57BL/6J mice. J Nutr. 2017 Nov;147(11):2041-2049
  Sellmann C, Baumann A, Brandt A, Jin CJ, Nier A, Bergheim I
  
• Oral arginine supplementation attenuates the progression of steatosis to non-alcoholic steatohepatitis through preventing translocation of bacterial endotoxin. EASL 2019, Vienna, Austria
  Baumann A, Rajcic D, Brandt A, Jung F, Nier A, Jin CJ, Bergheim I
  
• GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease, EASL 2020, online
  Baumann A, Brandt A, Rajcic D, Jung F, Nier A, Bergheim I
  
• Citrulline supplementation attenuates the development of nonalcoholic steatohepatitis in female mice through mechanisms involving intestinal arginase. Redox Biol. 2021 May;41:101879
  Rajcic D, Baumann A, Hernández-Arriaga A, Brandt A, Nier A, Jin CJ, Sánchez V, Jung F, Camarinha-Silva A, Bergheim I