https://www.sciencedirect.com/science/article/pii/S2212877826000098
HIGHLIGHTS
- •Dietary SAAR increases glucose partitioning to liver de novo serine synthesis.
- •Deletion of liver PSAT1 abrogates improvements in glucose tolerance by SAAR.
- •SAAR lowers lysine lactoylation, a SAA-supported post-translational modification known to inhibit serine synthesis enzymes.
- •Hepatic PSAT1 is not necessary for SAAR to lower adiposity and liver triglycerides.
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.
...
Elevated expression of liver de novo serine synthesis pathway enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), is among the most reproducible responses to dietary SAAR, making their increase a marker of a successful dietary intervention [2,9,10]; [[15], [16], [17], [18], [19], [20], [21], [22], [23]]. De novo serine synthesis is sourced from 3-phosphoglycerate, an intermediate of both glycolysis and gluconeogenesis [24]. Thus, a SAAR-mediated increase in hepatic serine synthesis could promote greater glucose disposal and/or divert gluconeogenic flux away from glucose production.
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