Kulaylat M N, Frexes-Steed M, Geer R, Williams P E, Abumrad N N
Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232.
Surgery. 1988 Mar;103(3):351-60.
Isolated hepatocyte studies demonstrated that leucine can be a precursor of ketone bodies. In this study we examine the relative contribution of leucine to hepatic ketogenesis in vivo. Three groups of conscious dogs with long-term indwelling catheters in the femoral artery, hepatic vein, and portal vein were studied. Group I (n = 3) animals were fasted overnight for 24 hours, and those in groups II and III (n = 4, each) were fasted for 62 to 68 hours (designated 3-day fast). Groups I and III received intravenous saline solution (0.9%) and served as controls. In group II selective acute insulin deficiency (SAID) was induced by a peripheral intravenous somatostatin (SRIF) infusion and intraportal glucagon (0.55 ng/body weight/min). Net hepatic production (NHP) of ketone bodies (kb) and leucine (leu) was measured by the arteriovenous difference technique. Hepatic conversion of leucine to ketone bodies was measured by continuous infusion of L-U-[14C]-leucine and by determination of the appearance of [14C]-ketone bodies across the liver. In the group fasted overnight NHPleu was 0.02 +/- 0.01 mumol/kg/min, a value not different from zero. NHPkb was 3.1 +/- 0.1 mumol/kg/min and hepatic conversion of leucine to ketone bodies accounted for 3.5% of NHPkb. Insulin deficiency after 3 day's fasting resulted in a near 70% increase in NHPleu (from basal values of 0.31 +/- 0.1 mumol/kg/min to 0.52 +/- 0.06 mumol/kg/min during SAID, p less than 0.01). NHPkb increased from 11.0 +/- 1.0 to 15.5 mumol/kg/min (p less than 0.05). The rate of leucine conversion to ketone bodies (L-C) increased from 1.1 +/- 0.25 to 2.4 +/- 0.3 mumol/kg/min (p less than 0.01) with SAID. We conclude that as the dog progresses to fasting, the contribution of leucine carbon to hepatic production of ketone bodies increases from 3.5% to 10% (p less than 0.01), and this value increases to 15% (p less than 0.01 versus groups I and II) after SAID. Furthermore, the amount of leucine carbon taken up by the liver was not sufficient to account for all [14C]-labeled leucine to ketone bodies. The data suggest that the leucine carbon converted to ketone bodies must have been derived from intrahepatic protein sources of possibly from the keto acids of leucine, which are derived by the breakdown of leucine at distant sites, such as skeletal muscle or adipose tissue.
分离肝细胞研究表明，亮氨酸可以是酮体的前体。在本研究中，我们检测了亮氨酸在体内对肝脏生酮作用的相对贡献。研究了三组有意识的犬，其股动脉、肝静脉和门静脉长期留置导管。第一组（n = 3）动物禁食过夜24小时，第二组和第三组（每组n = 4）禁食62至68小时（称为3天禁食）。第一组和第三组接受静脉注射生理盐水（0.9%）作为对照。在第二组中，通过外周静脉输注生长抑素（SRIF）和门静脉内注射胰高血糖素（0.55 ng/体重/分钟）诱导选择性急性胰岛素缺乏（SAID）。通过动静脉差值技术测量肝脏酮体（kb）和亮氨酸（leu）的净生成量（NHP）。通过持续输注L-U-[14C]-亮氨酸并测定[14C]-酮体在肝脏中的出现情况来测量亮氨酸向酮体的肝脏转化率。在禁食过夜的组中，NHPleu为0.02±0.01 μmol/kg/分钟，该值与零无差异。NHPkb为3.1±0.1 μmol/kg/分钟，亮氨酸向酮体的肝脏转化率占NHPkb的3.5%。禁食3天后的胰岛素缺乏导致NHPleu增加近70%（从基础值0.31±0.1 μmol/kg/分钟增加到SAID期间的0.52±0.06 μmol/kg/分钟，p<0.01）。NHPkb从11.0±1.0增加到15.5 μmol/kg/分钟（p<0.05）。SAID时，亮氨酸转化为酮体的速率（L-C）从1.1±0.25增加到2.4±0.3 μmol/kg/分钟（p<0.01）。我们得出结论，随着犬进入禁食状态，亮氨酸碳对肝脏酮体生成的贡献从3.5%增加到10%（p<0.01），SAID后该值增加到15%（与第一组和第二组相比，p<0.01）。此外，肝脏摄取的亮氨酸碳量不足以解释所有[14C]标记的亮氨酸转化为酮体的情况。数据表明，转化为酮体的亮氨酸碳一定来自肝脏内的蛋白质来源，可能来自亮氨酸的酮酸，而亮氨酸的酮酸是由亮氨酸在远处部位（如骨骼肌或脂肪组织）分解产生的。
