Department of Medicine, Division of Gastroenterology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
FASEB J. 2012 May;26(5):2209-21. doi: 10.1096/fj.11-202853. Epub 2012 Feb 17.
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.
酰基辅酶 A 硫酯酶（Acot）基因家族的成员催化脂肪酸酰基辅酶 A 的水解，但它们的生物学功能仍不清楚。硫酯酶超家族成员 2（Them2；同义词 Acot13）是一种广泛表达的与线粒体相关的 Acot。Them2 先前被鉴定为磷脂酰胆碱转移蛋白（PC-TP）的相互作用蛋白。Pctp（-/-）小鼠表现出改变的脂肪酸代谢，伴随着肝葡萄糖产生减少。为了研究 Them2 在调节肝脂质和葡萄糖稳态中的作用，我们生成了 Them2（-/-）小鼠。与 Them2（+/+）对照相比，Them2（-/-）小鼠肝脏中线粒体硫酯酶活性的 K(m)增加了 1.9 倍，脂肪酸酰基辅酶 A 浓度增加了 28%。游离脂肪酸浓度相应降低了 23%，与过氧化物酶体增殖物激活受体 α 的激活减少有关。然而，Them2（-/-）小鼠肝脏中的脂肪酸氧化率保持不变，表明 Them2 可限制β氧化。在肝细胞核因子 4α（HNF4α）表达减少的情况下，肝葡萄糖生成也降低了 45%。当喂食高脂肪饮食时，Them2（-/-）小鼠对肝葡萄糖生成和脂肪变性的增加具有抵抗力。这些发现揭示了 Them2 在调节肝脏代谢中的关键作用，这些作用可能是通过 PC-TP-Them2 相互作用介导的。
