α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism.
Coordinated gastrointestinal smooth muscle contraction is critical for proper nutrient absorption and is altered in a number of medical disorders. In this work, we demonstrate a critical role for the RGD-binding integrin α8β1 in promoting nutrient absorption through regulation of gastrointestinal motility. Smooth muscle-specific deletion and antibody blockade of α8 in mice result in enhanced gastric antral smooth muscle contraction, more rapid gastric emptying, and more rapid transit of food through the small intestine leading to malabsorption of dietary fats and carbohydrates as well as protection from weight gain in a diet-induced model of obesity. Mechanistically, ligation of α8β1 by the milk protein Mfge8 reduces antral smooth muscle contractile force by preventing RhoA activation through a PTEN-dependent mechanism. Collectively, our results identify a role for α8β1 in regulating gastrointestinal motility and identify α8 as a potential target for disorders characterized by hypo- or hyper-motility.
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.|Department of Medicine, University of California, San Francisco, San Francisco, United States.
Amin
A
Khalifeh-Soltani
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
Arnold
A
Ha
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.|Department of Medicine, University of California, San Francisco, San Francisco, United States.
Michael J
MJ
Podolsky
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
Donald A
DA
McCarthy
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
William
W
McKleroy
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
Saeedeh
S
Azary
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
Stephen
S
Sakuma
Metabolic Biology, University of California, Berkeley, Berkeley, United States.|Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States.
Kevin M
KM
Tharp
Lung Biology Center, University of California, San Francisco, San Francisco, United States.
Nanyan
N
Wu
Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Health Administration Center, Hiroshima University, Hiroshima, Japan.
Yasuyuki
Y
Yokosaki
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.
Daniel
D
Hart
Metabolic Biology, University of California, Berkeley, Berkeley, United States.|Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States.
Andreas
A
Stahl
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.|Department of Medicine, University of California, San Francisco, San Francisco, United States.|Lung Biology Center, University of California, San Francisco, San Francisco, United States.
Kamran
0000-0001-8170-7881
K
Atabai
D000327:Adsorption; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D005502:Food; D005769:Gastrointestinal Motility; D041981:Gastrointestinal Tract / Q000502:physiology; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*
D000954:Antigens, Surface; D016023:Integrins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; C094866:integrin alpha8beta1; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
Mfge8; PTEN; cell biology; gastrointestinal motility; human; integrin; mouse; nutrient absorption; smooth muscle