MFGE8 links absorption of dietary fatty acids with catabolism of enterocyte lipid stores through HNF4y-dependent transcription of CES enzymes

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 activa-tion of triglyceride (TG) hydrolases that catabolize cLDs for chylomicron production. Here, we identify CES1D as the key hydrolase downstream of the MFGE8-orv85 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 HNF4y. Both Ces1d and Hnf4g KO mice have decreased enterocyte TG hydrolase activity coupled with retention of TG in cLDs. Mechanistically, MFGE8-dependent fatty acid uptake through CD36 stabilizes HNF4y protein level; HNF4y 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.

Automated summary

Enterocytes regulate postprandial lipemia by storing dietary fats in cytoplasmic lipid droplets and utilizing MFGE8 to activate hydrolases for catabolism. CES1D is identified as the key hydrolase downstream of the MFGE8-orv85 integrin pathway. The stabilization of HNF4y by MFGE8-dependent fatty acid uptake through CD36 leads to increased Ces1d transcription. This study uncovers a regulatory network that links dietary fat absorption with the expression of hydrolases responsible for catabolizing diet-derived lipid droplets.