The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse

Abstract

The Thiamine Transporter 2 (THTR2) encoded by SLC19A3 plays an ill-defined role in the maintenance of tissue thiamine, thiamine monophosphate, and thiamine diphosphate (TDP) levels. To evaluate the impact of THTR2 on tissue thiamine status and metabolism, we expressed the human SLC19A3 transgene in the intestine of total body Slc19a3 knockout (KO) mice. Male and female wildtype (WT) and transgenic (TG) mice were fed either 17 mg/kg (1×) or 85 mg/kg (5×) thiamine hydrochloride diet, while KOs were only fed the 5× diet. Thiamine vitamers in plasma, red blood cells, duodenum, brain, liver, kidney, heart, and adipose tissue were measured. Untargeted metabolomics were performed on the brain tissues of groups with equivalent plasma thiamine. KO mice had ~two- and ~three-fold lower plasma and brain thiamine levels than WT on the 5× diet. Circulating vitamers were sensitive to diet and equivalent in TG and WT mice. However, TG had 60% lower thiamine but normal brain TDP levels regardless of diet, with subtle differences in the heart and liver. The loss of THTR2 reduced levels of nucleic acid and amino acid derivatives in the brain. Therefore, mutation or inhibition of THTR2 may alter the brain metabolome and reduce the thiamine reservoir for TDP biosynthesis.

Keywords

• thiamine
• thiamine transporter 2
• THTR2
• brain metabolism
• metabolomics