MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes
Ritwik Datta,
Mohammad A. Gholampour,
Christopher D. Yang,
Regan Volk,
Sinan Lin,
Michael J. Podolsky,
Thomas Arnold,
Florian Rieder,
Balyn W. Zaro,
Michael Verzi,
Richard Lehner,
Nada Abumrad,
Carlos O. Lizama,
Kamran Atabai
Affiliations
Ritwik Datta
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Mohammad A. Gholampour
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Christopher D. Yang
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Regan Volk
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Sinan Lin
Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Michael J. Podolsky
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Thomas Arnold
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA
Florian Rieder
Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Balyn W. Zaro
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Michael Verzi
Rutgers University, New Brunswick, NJ 08854, USA
Richard Lehner
Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
Nada Abumrad
Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
Carlos O. Lizama
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
Kamran Atabai
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; Corresponding author
Summary: Enterocytes modulate the extent of postprandial lipemia by storing dietary fats in cytoplasmic lipid droplets (cLDs). We have previously shown that the integrin ligand MFGE8 links absorption of dietary fats with activation of triglyceride (TG) hydrolases that catabolize cLDs for chylomicron production. Here, we identify CES1D as the key hydrolase downstream of the MFGE8-αvβ5 integrin pathway that regulates catabolism of diet-derived cLDs. Mfge8 knockout (KO) enterocytes have reduced CES1D transcript and protein levels and reduced protein levels of the transcription factor HNF4γ. Both Ces1d and Hnf4γ KO mice have decreased enterocyte TG hydrolase activity coupled with retention of TG in cLDs. Mechanistically, MFGE8-dependent fatty acid uptake through CD36 stabilizes HNF4γ protein level; HNF4γ then increases Ces1d transcription. Our work identifies a regulatory network that regulates the severity of postprandial lipemia by linking dietary fat absorption with protein stabilization of a transcription factor that increases expression of hydrolases responsible for catabolizing diet-derived cLDs.
