A Comparison Between Canonical and Alternative Pathways in Triglyceride Synthesis

Background: Mammals have evolved the ability to store and transport energy as triglycerides (TGs). TG synthesis occurs primarily in the liver during fasting and in white adipose tissue (WAT) following feeding. In humans, the last step of the canonical pathway in TG synthesis is carried out by diacylglycerol O-acyltransferase 1 (DGAT1) and DGAT2, which catalyze the covalent addition of a fatty acyl chain to diacylglycerol in both the liver and WAT. Recently, an alternative TG synthesis pathway was discovered: transmembrane protein 68 (TMEM68) carries out cell-autonomous TG synthesis, with thioredoxin-related transmembrane protein 1 (TMX1) being its inhibitor. Methods: Because TG synthesis in the body is tightly and accurately regulated, we compared and contrasted the expressions of genes involved in the two pathways during the fed-fast cycle in the liver and WAT of mice, in mice treated with a high-fat diet (HFD), and in young vs. old mice. Results: We found that in the liver, fasting upregulated Dgat1 , Dgat2 , and Tmx1 , while in WAT it reduced Dgat2 but increased Tmx1 . Moreover, HFD and aging suppressed the expression of Dgat1 and Dgat2 in WAT. Male Tmem68 knockout mice generated by the International Mouse Phenotypic Consortium exhibited elevated plasma aspartate aminotransferase (AST) levels and reduced glucose levels, suggesting potential liver and glucose homeostasis abnormalities. Conclusions: Our results are consistent with the notion that during fasting, the liver relies more on the canonical pathway and that in WAT, both pathways are upregulated following feeding. J Endocrinol Metab. 2024;14(5):250-257 doi: https://doi.org/10.14740/jem1017