Integrin α1-null mice exhibit improved fatty liver when fed a high fat diet despite severe hepatic insulin resistance.

Williams AS, Kang L, Zheng J, Grueter C, Bracy DP, James FD, Pozzi A, Wasserman DH
J Biol Chem. 2015 290 (10): 6546-57

PMID: 25593319 · PMCID: PMC4358288 · DOI:10.1074/jbc.M114.615716

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.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

MeSH Terms (13)

Animals Diet, High-Fat Fatty Liver Glucose Hepatocytes Humans Insulin Insulin Resistance Integrin alpha1 Liver Mice Mice, Knockout Triglycerides

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