University of Utah Molecular Medicine (U2M2) Program, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84112, USA.
Genes Dev. 2012 Feb 1;26(3):282-93. doi: 10.1101/gad.180968.111.
To find new genes that influence liver lipid mass, we performed a genetic screen for zebrafish mutants with hepatic steatosis, a pathological accumulation of fat. The red moon (rmn) mutant develops hepatic steatosis as maternally deposited yolk is depleted. Conversely, hepatic steatosis is suppressed in rmn mutants by adequate nutrition. Adult rmn mutants show increased liver neutral lipids and induction of hepatic lipid biosynthetic genes when fasted. Positional cloning of the rmn locus reveals a loss-of-function mutation in slc16a6a (solute carrier family 16a, member 6a), a gene that we show encodes a transporter of the major ketone body β-hydroxybutyrate. Restoring wild-type zebrafish slc16a6a expression or introducing human SLC16A6 in rmn mutant livers rescues the mutant phenotype. Radiotracer analysis confirms that loss of Slc16a6a function causes diversion of liver-trapped ketogenic precursors into triacylglycerol. Underscoring the importance of Slc16a6a to normal fasting physiology, previously fed rmn mutants are more sensitive to death by starvation than are wild-type larvae. Our unbiased, forward genetic approach has found a heretofore unrecognized critical step in fasting energy metabolism: hepatic ketone body transport. Since β-hydroxybutyrate is both a major fuel and a signaling molecule in fasting, the discovery of this transporter provides a new direction for modulating circulating levels of ketone bodies in metabolic diseases.
为了寻找影响肝脏脂质质量的新基因，我们对发生肝脂肪变性（即脂肪病理性堆积）的斑马鱼突变体进行了遗传筛选。红月亮（rmn）突变体在卵黄耗尽时会发生肝脂肪变性。相反，当 rmn 突变体得到充足的营养时，其肝脂肪变性会受到抑制。在禁食状态下，成年 rmn 突变体的肝脏中性脂质增加，肝脏脂质生物合成基因被诱导。rmn 基因座的定位克隆显示 slc16a6a（溶质载体家族 16a，成员 6a）发生功能丧失突变，该基因编码主要酮体β-羟丁酸的转运体。野生型斑马鱼 slc16a6a 表达的恢复或 rmn 突变体肝脏中人类 SLC16A6 的引入可挽救突变表型。示踪剂分析证实 Slc16a6a 功能的丧失导致肝脏捕获的生酮前体转向三酰甘油。鉴于 Slc16a6a 对正常禁食生理的重要性，之前喂养的 rmn 突变体比野生型幼虫更容易因饥饿而死亡。我们的无偏正向遗传方法发现了禁食能量代谢中一个以前未被认识的关键步骤：肝脏酮体转运。由于β-羟丁酸既是禁食时的主要燃料又是信号分子，该转运体的发现为调节代谢性疾病中酮体的循环水平提供了一个新方向。
