title: Integrin α1-null mice exhibit improved fatty liver when fed a high fat diet despite severe hepatic insulin resistance.
abstract: Hepatic insulin resistance is associated with increased collagen. Integrin α1β1 is a collagen-binding receptor expressed on hepatocytes. Here, we show that expression of the α1 subunit is increased in hepatocytes isolated from high fat (HF)-fed mice. To determine whether the integrin α1 subunit protects against impairments in hepatic glucose metabolism, we analyzed glucose tolerance and insulin sensitivity in HF-fed integrin α1-null (itga1(-/-)) and wild-type (itga1(+/+)) littermates. Using the insulin clamp, we found that insulin-stimulated hepatic glucose production was suppressed by ∼50% in HF-fed itga1(+/+) mice. In contrast, it was not suppressed in HF-fed itga1(-/-) mice, indicating severe hepatic insulin resistance. This was associated with decreased hepatic insulin signaling in HF-fed itga1(-/-) mice. Interestingly, hepatic triglyceride and diglyceride contents were normalized to chow-fed levels in HF-fed itga1(-/-) mice. This indicates that hepatic steatosis is dissociated from insulin resistance in HF-fed itga1(-/-) mice. The decrease in hepatic lipid accumulation in HF-fed itga1(-/-) mice was associated with altered free fatty acid metabolism. These studies establish a role for integrin signaling in facilitating hepatic insulin action while promoting lipid accumulation in mice challenged with a HF diet.
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and ashley.s.williams@vanderbilt.edu.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Williams
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Anesthesiology.
authors.forename: Carrie
authors.initials: C
authors.lastname: Grueter
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and.
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and.
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and Division of Nephrology, Department of Medicine, and the Department of Medicine, Department of Veteran Affairs, Nashville, Tennessee 37212-2637.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.affiliation: From the Departments of Molecular Physiology and Biophysics and Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, Tennessee 37232 and.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D039423:Integrin alpha1 / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007328:Insulin; D039423:Integrin alpha1; D014280:Triglycerides; D005947:Glucose
keywords: Extracellular Matrix; Insulin Resistance; Integrin; Lipid Metabolism; Liver Metabolism