Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis

Abstract

Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic de novo serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein ([~]70-fold), serine concentration ([~]2-fold), and 13C-serine ([~]20-fold) following an intravenous infusion of [U-13C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR. Graphical AbstractSchematic representation of liver glucose adaptations to SAAR O_FIG O_LINKSMALLFIG WIDTH=132 HEIGHT=200 SRC="FIGDIR/small/682938v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@dcda30org.highwire.dtl.DTLVardef@1789003org.highwire.dtl.DTLVardef@36cd4eorg.highwire.dtl.DTLVardef@1e0c640_HPS_FORMAT_FIGEXP M_FIG C_FIG