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other·preclinical research, biomedical research, gastroenterology, cardiology, endocrinology·PMC10138282

MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes

Cell reports · 14 authors, 8 centres

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Using Mfge8, Ces1d, Hnf4γ, Atgl, and Cd36 knockout mice, the authors delineate a pathway in which MFGE8 ligation of αvβ5 integrin and CD36-mediated fatty acid uptake stabilize the intestinal transcription factor HNF4γ, which in turn drives transcription of Ces1d and related Ces1-family hydrolases. Ces1d and Hnf4γ knockout mice phenocopied these defects, and Cd36 knockout enterocytes showed similar reductions in HNF4γ and CES1D protein and triglyceride hydrolase activity.

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preclinical research

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ORIGINAL PAPER

PMC10138282

MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes

Cell reports

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ABSTRACT

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 Hnf4 γ 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.

CITATION EXPORT

Ritwik Datta, Mohammad A. Gholampour, Christopher D. Yang et al.. MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4γ-dependent transcription of CES enzymes. Cell reports. (2023). https://doi.org/10.1016/j.celrep.2023.112249

AUTHORS

14 · 8 CENTRES

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

1Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA
2Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
3Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA
4Rutgers University, New Brunswick, NJ 08854, USA
5Department of Pediatrics, University of Alberta, Edmonton, AB T6G 1C9, Canada
6Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA
7Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA
8Lead contact