Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity.
The small intestine has an underappreciated role as a lipid storage organ. Under conditions of high dietary fat intake, enterocytes can minimize the extent of postprandial lipemia by storing newly absorbed dietary fat in cytoplasmic lipid droplets. Lipid droplets can be subsequently mobilized for the production of chylomicrons. The mechanisms that regulate this process are poorly understood. We report here that the milk protein Mfge8 regulates hydrolysis of cytoplasmic lipid droplets in enterocytes after interacting with the αvβ3 and αvβ5 integrins. Mice deficient in Mfge8 or the αvβ3 and αvβ5 integrins accumulate excess cytoplasmic lipid droplets after a fat challenge. Mechanistically, interruption of the Mfge8-integrin axis leads to impaired enterocyte intracellular triglyceride hydrolase activity in vitro and in vivo. Furthermore, Mfge8 increases triglyceride hydrolase activity through a PI3 kinase/mTORC2-dependent signaling pathway. These data identify a key role for Mfge8 and the αvβ3 and αvβ5 integrins in regulating enterocyte lipid processing.
Department of Medicine.|Cardiovascular Research Institute.|Lung Biology Center, University of California, San Francisco, San Francisco, California, USA.
Amin
A
Khalifeh-Soltani
Department of Medicine.|Cardiovascular Research Institute.|Lung Biology Center, University of California, San Francisco, San Francisco, California, USA.
Deepti
D
Gupta
Department of Medicine.|Cardiovascular Research Institute.
Arnold
A
Ha
Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York, USA.
Jahangir
J
Iqbal
Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York, USA.
Mahmood
M
Hussain
Department of Medicine.|Cardiovascular Research Institute.|Lung Biology Center, University of California, San Francisco, San Francisco, California, USA.
Michael J
MJ
Podolsky
Department of Medicine.|Cardiovascular Research Institute.|Lung Biology Center, University of California, San Francisco, San Francisco, California, USA.
Kamran
K
Atabai
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D018938:Caco-2 Cells; D002914:Chylomicrons; D020895:Enterocytes / Q000201:enzymology*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism; D014280:Triglycerides
D000954:Antigens, Surface; D002914:Chylomicrons; D039302:Integrin alphaVbeta3; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D019030:Receptors, Vitronectin; D014280:Triglycerides; C064660:integrin alphaVbeta5; D006867:Hydrolases