Akiyoshi Fukamizu

Publications (2)53.63 Total impact

• Article: ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation.

  Tatsuo Hashimoto, Thomas Perlot, Ateequr Rehman, Jean Trichereau, Hiroaki Ishiguro, Magdalena Paolino, Verena Sigl, Toshikatsu Hanada, Reiko Hanada, Simone Lipinski, [......], Simone M R Camargo, Dustin Singer, Andreas Richter, Keiji Kuba, Akiyoshi Fukamizu, Stefan Schreiber, Hans Clevers, Francois Verrey, Philip Rosenstiel, Josef M Penninger
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  ABSTRACT: Malnutrition affects up to one billion people in the world and is a major cause of mortality. In many cases, malnutrition is associated with diarrhoea and intestinal inflammation, further contributing to morbidity and death. The mechanisms by which unbalanced dietary nutrients affect intestinal homeostasis are largely unknown. Here we report that deficiency in murine angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (Ace2), which encodes a key regulatory enzyme of the renin-angiotensin system (RAS), results in highly increased susceptibility to intestinal inflammation induced by epithelial damage. The RAS is known to be involved in acute lung failure, cardiovascular functions and SARS infections. Mechanistically, ACE2 has a RAS-independent function, regulating intestinal amino acid homeostasis, expression of antimicrobial peptides, and the ecology of the gut microbiome. Transplantation of the altered microbiota from Ace2 mutant mice into germ-free wild-type hosts was able to transmit the increased propensity to develop severe colitis. ACE2-dependent changes in epithelial immunity and the gut microbiota can be directly regulated by the dietary amino acid tryptophan. Our results identify ACE2 as a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology, and transmissible susceptibility to colitis. These results provide a molecular explanation for how amino acid malnutrition can cause intestinal inflammation and diarrhoea.
  Nature 07/2012; 487(7408):477-81. · 36.28 Impact Factor
• Article: Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity.

  Lale Ozcan, Catherine C L Wong, Gang Li, Tao Xu, Utpal Pajvani, Sung Kyu Robin Park, Anetta Wronska, Bi-Xing Chen, Andrew R Marks, Akiyoshi Fukamizu, Johannes Backs, Harold A Singer, John R Yates, Domenico Accili, Ira Tabas
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  ABSTRACT: Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis.
  Cell metabolism 04/2012; 15(5):739-51. · 17.35 Impact Factor