α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism

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Abstract

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.

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Amin Khalifeh-Soltani

Medicine, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Arnold Ha

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Michael J Podolsky

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Donald A McCarthy

Department of Medicine, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
William McKleroy

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Saeedeh Azary

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Stephen Sakuma

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

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The authors declare that no competing interests exist.
Kevin M Tharp

Metabolic Biology, University of California, Berkeley, Berkeley, United States

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The authors declare that no competing interests exist.
Nanyan Wu

Lung Biology Center, University Of California, San Francisco, San Fransico, United States

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The authors declare that no competing interests exist.
Yasuyuki Yokosaki

Cell-Matrix Frontier Laboratory, Biomedical Research Unit, Health Administration Center, Hiroshima University, Hiroshima, Japan

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The authors declare that no competing interests exist.
Daniel O Hart

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Andreas Stahl

Metabolic Biology, University of California, Berkeley, Berkeley, United States

Competing interests
The authors declare that no competing interests exist.
Kamran Atabai

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States

For correspondence
kamran.atabai@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal experiments were approved by the UCSF Institutional Animal Care and Use Committee in adherence to NIH guidelines and policies.(#AN109941-01A)

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.