ABSTRACT
Use of yttrium-90 (Y-90) is used for primary liver tumors and a handful of liver metastatic lesions. Y-90 treatment for metastatic adrenocortical carcinoma (ACC) to the liver is currently off-label, with one previously documented case report. In this case report, we present a 52-year-old woman with ACC and extensive liver metastatic disease. After failed chemotherapy, multidisciplinary discussion suggested potential Y-90 treatment for palliative purposes. After undergoing Y-90 treatment separately to the right and then the left hepatic lobes, subsequent patient visits demonstrated significantly improved clinical function as well as complete radiographic resolution of liver metastatic disease mainly from ACC. This case report demonstrates the potential efficacy of Y-90 for off-label uses in liver metastatic disease. This case and similar cases may open the door to a wide variety of potential indications for Y-90 treatment.
ABSTRACT
Protein-tyrosine phosphatase 1B (PTP1B) is a physiological regulator of glucose homeostasis and adiposity and is a drug target for the treatment of obesity and diabetes. Here we identify pyruvate kinase M2 (PKM2) as a novel PTP1B substrate in adipocytes. PTP1B deficiency leads to increased PKM2 total tyrosine and Tyr(105) phosphorylation in cultured adipocytes and in vivo. Substrate trapping and mutagenesis studies identify PKM2 Tyr-105 and Tyr-148 as key sites that mediate PTP1B-PKM2 interaction. In addition, in vitro analyses illustrate a direct effect of Tyr-105 phosphorylation on PKM2 activity in adipocytes. Importantly, PTP1B pharmacological inhibition increased PKM2 Tyr-105 phosphorylation and decreased PKM2 activity. Moreover, PKM2 Tyr-105 phosphorylation is regulated nutritionally, decreasing in adipose tissue depots after high-fat feeding. Further, decreased PKM2 Tyr-105 phosphorylation correlates with the development of glucose intolerance and insulin resistance in rodents, non-human primates, and humans. Together, these findings identify PKM2 as a novel substrate of PTP1B and provide new insights into the regulation of adipose PKM2 activity.
Subject(s)
Phosphotyrosine/metabolism , Protein Processing, Post-Translational , Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism , Pyruvate Kinase/metabolism , 3T3-L1 Cells , Adipose Tissue, Brown/enzymology , Adult , Aged , Amino Acid Substitution , Animals , Diet, High-Fat , Energy Metabolism , Gene Knockdown Techniques , Glucose Intolerance , Humans , Insulin Resistance , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Phosphorylation , Protein Interaction Domains and Motifs , Protein Interaction Mapping , Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry , Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics , Pyruvate Kinase/chemistry , Pyruvate Kinase/genetics , Signal TransductionABSTRACT
Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose inhibition has beneficial effects in cardiovascular, inflammatory, and metabolic diseases in murine models. Mice with targeted deletion or pharmacological inhibition of sEH exhibit improved insulin signaling in liver and adipose tissue. Herein, we assessed the role of sEH in regulating endoplasmic reticulum (ER) stress in liver and adipose tissue. We report that sEH expression was increased in the livers and adipose tissue of mice fed a high fat diet, the adipose tissue of overweight humans, and palmitate-treated cells. Importantly, sEH deficiency or inhibition in mice attenuated chronic high fat diet-induced ER stress in liver and adipose tissue. Similarly, pharmacological inhibition of sEH in HepG2 cells and 3T3-L1 adipocytes mitigated chemical-induced ER stress and activation of JNK, p38, and cell death. In addition, insulin signaling was enhanced in HepG2 cells treated with sEH substrates and attenuated in cells treated with sEH products. In summary, these findings demonstrate that sEH is a physiological modulator of ER stress and a potential target for mitigating complications associated with obesity.
