Publications (2)17.38 Total impact
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Article: Thioesterase superfamily member 2/acyl-CoA thioesterase 13 (Them2/Acot13) regulates hepatic lipid and glucose metabolism.
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ABSTRACT: Members of the acyl-CoA thioesterase (Acot) gene family catalyze the hydrolysis of fatty acyl-CoAs, but their biological functions remain unknown. Thioesterase superfamily member 2 (Them2; synonym Acot13) is a broadly expressed mitochondria-associated Acot. Them2 was previously identified as an interacting protein of phosphatidylcholine transfer protein (PC-TP). Pctp(-/-) mice exhibit altered fatty acid metabolism that is accompanied by reduced hepatic glucose production. To examine the role of Them2 in regulating hepatic lipid and glucose homeostasis, we generated Them2(-/-) mice. In livers of Them2(-/-) mice compared with Them2(+/+) controls, a 1.9-fold increase in the K(m) of mitochondrial thioesterase activity was accompanied by a 28% increase in fatty acyl-CoA concentration. A reciprocal 23% decrease in free fatty acid concentration was associated with reduced activation of peroxisome proliferator-activated receptor α. However, fatty acid oxidation rates were preserved in livers of Them2(-/-) mice, suggesting that Them2 functions to limit β-oxidation. Hepatic glucose production was also decreased by 45% in the setting of reduced hepatocyte nuclear factor 4α (HNF4α) expression. When fed a high-fat diet, Them2(-/-) mice were resistant to increases in hepatic glucose production and steatosis. These findings reveal key roles for Them2 in the regulation of hepatic metabolism, which are potentially mediated by PC-TP-Them2 interactions.The FASEB Journal 02/2012; 26(5):2209-21. · 5.71 Impact Factor -
Article: Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production.
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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.Hepatology 04/2011; 54(2):664-74. · 11.66 Impact Factor
