Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet?induced hepatic glucose production†‡

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dc.contributor.authorShishova, Ekaterina Y
dc.contributor.authorStoll, Janis M.
dc.contributor.authorErsoy, Baran A.
dc.contributor.authorShrestha, Sudeep
dc.contributor.authorScapa, Erez F.
dc.contributor.authorLi, Yingxia
dc.contributor.authorNiepel, Michele W.
dc.contributor.authorSu, Ya
dc.contributor.authorJelicks, Linda A.
dc.contributor.authorStahl, Gregory L.
dc.contributor.authorGlicksman, Marcie A.
dc.contributor.authorGutierrez-Juarez, Roger
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorCohen, David E.
dc.date.accessioned2020-03-10T17:31:39Z
dc.date.available2020-03-10T17:31:39Z
dc.date.issued2012-08
dc.description.abstract Phosphatidylcholine transfer protein (PC?TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp?/? mice are protected against diet?induced increases in hepatic glucose production and that small molecule inhibition of PC?TP recapitulates this phenotype. Pctp?/? and wildtype mice were subjected to high?fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high?fat diet?induced increases in hepatic glucose production were markedly attenuated in Pctp?/? mice. Small molecule inhibitors of PC?TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high?fat?fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC?TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high?fat feeding, but had no activity in Pctp?/? mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin?sensitizing agents, the inhibitor promoted insulin?independent phosphorylation of key insulin signaling molecules. Conclusion: These findings suggest PC?TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance.
dc.identifier.citationCopyright 2011 Hepatology. This is a post-print version of a published paper that is available at: https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.24393. Recommended citation: Shishova, Ekaterina Y., Janis M. Stoll, Baran A. Ersoy, Sudeep Shrestha, Erez F. Scapa, Yingxia Li, Michele W. Niepel et al. "Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet?induced hepatic glucose production." Hepatology 54, no. 2 (2011): 664-674. doi: 10.1002/hep.24393. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.
dc.identifier.urihttps://hdl.handle.net/10657/5960
dc.language.isoen_US
dc.publisherHepatology
dc.subjectobesity
dc.subjectinsulin resistance
dc.subjectdiabetes
dc.subjectStARD2
dc.subjectlipid binding protein
dc.titleGenetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet?induced hepatic glucose production†‡
dc.typeArticle

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