Hugo, S.E., Cruz-Garcia, L., Karanth, S., Anderson, R.M., Stainier, D.Y., and Schlegel, A. (2012) A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes & Development. 26(3):282-93.
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.