Abstract
When fasted as larvae or fed ketogenic diets as adults, homozygous zebrafish slc16a6a mutants develop hepatic steatosis because their livers cannot export the major ketone body β-hydroxybutyrate, diverting liver-trapped ketogenic carbon atoms to triacylglycerol. Here, we find that slc16a6a mutants are longer than their wild-type siblings. This effect is largely not sexually dimorphic, nor is it affected by dietary fat content on a pure genetic background. A mixed genetic background alters the proportionality of mass to length modestly. We also observe that non-coding variations in the 5′-untranslated region and first intron, and coding variations within the fifth exon of the orthologous human gene locus SLC16A6 are highly significantly associated with human height. Since both zebrafish and human orthologs of SLC16A6 are expressed in multiple locations, this gene likely regulates height through modulating transport of monocarboxylic acids in several tissues.
Highlights
We isolated a zebrafish mutant with nutritionally suppressible hepatic steatosis, revealing that the liver has a dedicated β-hydroxybutyrate transporter required during fasting, Slc16a6a (Hugo et al, 2012)
We present 5 -untranslated region (UTR), first intronic, and missense fifth-exonic variations in the SLC16A6 gene that are associated with human adult height
Homozygous WT WIK siblings of slc16a6−/− animals were used as a comparators in one cohort of animals that were genotyped at 3 months post-fertilization and sorted into equal density housing tanks as we described previously (Karanth et al, 2013)
Summary
We isolated a zebrafish mutant with nutritionally suppressible hepatic steatosis, revealing that the liver has a dedicated β-hydroxybutyrate transporter required during fasting, Slc16a6a (Hugo et al, 2012). The hepatic steatosis phenotype in slc16a6−/− larvae could be rescued by forced expression of both the wild-type (WT) zebrafish slc16a6a and the orthologous human SLC16A6 cDNAs in the livers of mutants. We find that in human population genetic studies, the SLC16A6 locus is strongly associated with human height.
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