Drosophila HNF4 acts in distinct tissues to direct a switch between lipid storage and export in the gut
Maximilian C. Vonolfen,
Fenja L. Meyer zu Altenschildesche,
Hyuck-Jin Nam,
Susanne Brodesser,
Akos Gyenis,
Jan Buellesbach,
Geanette Lam,
Carl S. Thummel,
Gilles Storelli
Affiliations
Maximilian C. Vonolfen
University of Cologne, Faculty of Mathematics and Natural Sciences, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany
Fenja L. Meyer zu Altenschildesche
University of Cologne, Faculty of Mathematics and Natural Sciences, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany
Hyuck-Jin Nam
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112-5330, USA
Susanne Brodesser
University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Akos Gyenis
University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany
Jan Buellesbach
Institute for Evolution & Biodiversity, University of Münster, Hüfferstrasse 1, 48149 Münster, Germany
Geanette Lam
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112-5330, USA
Carl S. Thummel
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112-5330, USA
Gilles Storelli
University of Cologne, Faculty of Mathematics and Natural Sciences, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany; Corresponding author
Summary: Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.
