Nuclear translocation ability of Lipin differentially affects gene expression and survival in fed and fasting Drosophila

Abstract

Lipins are eukaryotic proteins with functions in lipid synthesis and the homeostatic control of energy balance. They execute these functions by acting as phosphatidate phosphatase enzymes in the cytoplasm and by changing gene expression after translocation into the cell nucleus, in particular under fasting conditions. Here, we asked whether nuclear translocation and enzymatic activity of Drosophila Lipin serve essential functions and how gene expression changes, under both fed and fasting conditions, when nuclear translocation is impaired. To address these questions, we created a Lipin null mutant, a mutant expressing Lipin lacking a nuclear localization signal (LipinΔNLS), and a mutant expressing enzymatically dead Lipin. Our data support the conclusion that the enzymatic, but not the nuclear gene regulatory activity of Lipin, is essential for survival. Notably, adult LipinΔNLS flies were not only viable but also exhibited improved life expectancy. In contrast, they were highly susceptible to starvation. Both the improved life expectancy in the fed state and the decreased survival in the fasting state correlated with changes in metabolic gene expression. Moreover, increased life expectancy of fed flies was associated with a decreased metabolic rate. Interestingly, in addition to metabolic genes, genes involved in feeding behavior and the immune response were mis-regulated in LipinΔNLS flies. Combined, our data suggest that nuclear activity of Lipin influences the genomic response to nutrient availability with effects on life expectancy and starvation resistance. Thus, nutritional or therapeutic approaches that aim at lowering nuclear translocation of lipins in humans may be worth exploring.

Drosophila Lipase 3 Mediates the Metabolic Response to Starvation and Aging

“…In larvae, Lip3 expression is upregulated after 4 h starvation, but remains repressed under amino acid deprivation in the presence of carbohydrates ( Zinke et al, 2002 ). Lip3 is a target gene of Hepatocyte nuclear factor 4 (Hnf4), a transcription factor that regulates lipid mobilization and mitochondrial ß -oxidation upon starvation ( Palanker et al, 2009 ), and its starvation-dependent induction on nuclear translocation of Lipin, a protein required for lipid homeostasis ( Hood et al, 2020 ).…”

Starvation Decreases Immunity and Immune Regulatory Factor NF-κB in the Starlet Sea Anemone Nematostella vectensis

“…Downregulation of terms such as response to nutrient, lipid metabolic process, carbohydrate metabolic process, glycosylation GO:0070085, and proteolysis GO:0006508 under starvation conditions suggest an exhaustion of energetic sources. Downregulation of genes associated with metabolism of different energy sources (carbohydrates, lipids, proteins) during periods of starvation has been previously observed in other species 4,[39][40][41][42] . These downregulated GO terms indicate that the anemones in our experiments were indeed starved.…”

Comparative studies of genomic and epigenetic factors influencing transcriptional variation in two insect species

“…Following mean expression, the presence of a TATA box in the gene promoter region was a significant term in 12 of the 15 D. melanogaster datasets ( Supplementary Table 1 ) and in 6 of the 8 A. mellifera datasets ( Supplementary Table 1 ). The presence of a TATA box was positively and significantly correlated with gene expression variability in all but one study ( Hood et al 2020 ). The other core promoter element, presence of initiator motif, was only significant in approximately half of the studies (6 out of 12 D. melanogaster studies; 4 out of 8 A. mellifera studies; Supplementary Table 1 ).…”