Human metabolic disorders such as obesity and metabolic syndrome are linked to changes in fatty acid or cholesterol biosynthesis; processes controlled by the sterol regulatory element binding protein (SREBP) transcription factors. To study SREBP function in vivo, and to delineate SREBP transcriptional functions, we have examined SREBP (SBP-1) gene regulatory mechanisms in C. elegans, combined with complementary mechanistic studies in mammalian cell lines. SREBP activates genes important in cholesterol, fatty acid (FA) and phospholipid biosynthetic (PL) pathways and in production of co-factors such as Ac-CoA and NADPH. We have identified a novel set of SREBP-responsive genes in C. elegans and mammals, the methyl-group producing enzymes of the 1-carbon cycle (1-CC). We hypothesize SREBP regulates these genes because PL biogenesis requires methylation. Interference with the 1-CC in C. elegans disrupts lipid homeostasis, resulting in intestinal lipid accumulation. Importantly, this phenotype resembles lipid accumulation in human fatty liver disease. Co-regulation of the 1CC and lipid homeostasis may be a common impact point in metabolic disease. We have also investigated mechanisms of SREBP inhibition during fasting and found that SIRT1(
sir-2.1) limits fat production through direct deacetylation of SREBP, attenuating SREBP-dependent expression of FA biosynthetic genes. Furthermore, we found that C. elegans lacking functional
sir-2.1 (SIRT1), or treated with sirtuin inhibitors, retain fats during fasting. SBP-1 targets such as FA desaturase
fat-7 are inappropriately expressed during fasting in
sir-2.1(lof) animals or after treatment with sirtuin inhibitors. These mechanism are conserved; fasted Drosophila larvae lacking dSir2 (
sir-2.1) fail to downregulate dSREBP-dependent genes and retain fat body lipids. SREBP target gene expression increases after RNAi depletion or inhibition of SIRT1 in human cells and after SIRT1 depletion in murine liver during fasting. Thus, SIRT1/SIR-2.1/Sir2 plays an important conserved role in lipid homeostasis by shutting down SREBPs during fasting. These studies highlight the complex relationships between metabolic pathways in humans; delineating common control points will be key for designing treatments.