Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production

Ekaterina Y. Shishova, Janis M. Stoll, Baran A. Ersoy, Sudeep Shrestha, Erez F. Scapa, Yingxia Li, Michele W. Niepel, Ya Su, Linda A. Jelicks, Gregory L. Stahl, Marcie A. Glicksman, Roger Gutierrez-Juarez, Gregory D. Cuny, David E. Cohen

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)664-674
Number of pages11
JournalHepatology
Volume54
Issue number2
DOIs
StatePublished - Aug 2011

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Phospholipid Transfer Proteins
Diet
Glucose
Liver
Insulin
Fats
Insulin Resistance
Lipids
Glucose Clamp Technique
Glucose Intolerance
Protein Stability
High Fat Diet
Phosphatidylcholines
Pyruvic Acid
Carrier Proteins
Cell Culture Techniques
Hot Temperature
Binding Sites
Phosphorylation
Phenotype

ASJC Scopus subject areas

  • Hepatology

Cite this

Shishova, E. Y., Stoll, J. M., Ersoy, B. A., Shrestha, S., Scapa, E. F., Li, Y., ... Cohen, D. E. (2011). Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. Hepatology, 54(2), 664-674. https://doi.org/10.1002/hep.24393

Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. / Shishova, Ekaterina Y.; Stoll, Janis M.; Ersoy, Baran A.; Shrestha, Sudeep; Scapa, Erez F.; Li, Yingxia; Niepel, Michele W.; Su, Ya; Jelicks, Linda A.; Stahl, Gregory L.; Glicksman, Marcie A.; Gutierrez-Juarez, Roger; Cuny, Gregory D.; Cohen, David E.

In: Hepatology, Vol. 54, No. 2, 08.2011, p. 664-674.

Research output: Contribution to journalArticle

Shishova, EY, Stoll, JM, Ersoy, BA, Shrestha, S, Scapa, EF, Li, Y, Niepel, MW, Su, Y, Jelicks, LA, Stahl, GL, Glicksman, MA, Gutierrez-Juarez, R, Cuny, GD & Cohen, DE 2011, 'Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production', Hepatology, vol. 54, no. 2, pp. 664-674. https://doi.org/10.1002/hep.24393
Shishova, Ekaterina Y. ; Stoll, Janis M. ; Ersoy, Baran A. ; Shrestha, Sudeep ; Scapa, Erez F. ; Li, Yingxia ; Niepel, Michele W. ; Su, Ya ; Jelicks, Linda A. ; Stahl, Gregory L. ; Glicksman, Marcie A. ; Gutierrez-Juarez, Roger ; Cuny, Gregory D. ; Cohen, David E. / Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production. In: Hepatology. 2011 ; Vol. 54, No. 2. pp. 664-674.
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AU - Scapa, Erez F.

AU - Li, Yingxia

AU - Niepel, Michele W.

AU - Su, Ya

AU - Jelicks, Linda A.

AU - Stahl, Gregory L.

AU - Glicksman, Marcie A.

AU - Gutierrez-Juarez, Roger

AU - Cuny, Gregory D.

AU - Cohen, David E.

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