α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism
Amin Khalifeh-Soltani,
Arnold Ha,
Michael J Podolsky,
Donald A McCarthy,
William McKleroy,
Saeedeh Azary,
Stephen Sakuma,
Kevin M Tharp,
Nanyan Wu,
Yasuyuki Yokosaki,
Daniel Hart,
Andreas Stahl,
Kamran Atabai
Affiliations
Amin Khalifeh-Soltani
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United States
Arnold Ha
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Michael J Podolsky
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United States
Donald A McCarthy
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
William McKleroy
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Saeedeh Azary
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Stephen Sakuma
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Kevin M Tharp
Metabolic Biology, University of California, Berkeley, Berkeley, United States; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
Nanyan Wu
Lung Biology Center, University of California, San Francisco, San Francisco, United States
Yasuyuki Yokosaki
Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Health Administration Center, Hiroshima University, Hiroshima, Japan
Daniel Hart
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States
Andreas Stahl
Metabolic Biology, University of California, Berkeley, Berkeley, United States; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
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
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.
