Abstract
Lipin 1 regulates cellular lipid homeostasis through roles in glycerolipid synthesis (through phosphatidic acid phosphatase activity) and transcriptional coactivation. Lipin 1–deficient individuals exhibit episodic disease symptoms that are triggered by metabolic stress, such as stress caused by prolonged fasting. We sought to identify critical lipin 1 activities during fasting. We determined that lipin 1 deficiency induces widespread alternative mRNA splicing in liver during fasting, much of which is normalized by refeeding. The role of lipin 1 in mRNA splicing was largely independent of its enzymatic function. We identified interactions between lipin 1 and spliceosome proteins, as well as a requirement for lipin 1 to maintain homeostatic levels of spliceosome small nuclear RNAs and specific RNA splicing factors. In fasted Lpin1–/– liver, we identified a correspondence between alternative splicing of phospholipid biosynthetic enzymes and dysregulated phospholipid levels; splicing patterns and phospholipid levels were partly normalized by feeding. Thus, lipin 1 influences hepatic lipid metabolism through mRNA splicing, as well as through enzymatic and transcriptional activities, and fasting exacerbates the deleterious effects of lipin 1 deficiency on metabolic homeostasis.
Highlights
The regulation of lipid storage in mammalian tissues is critical for metabolic homeostasis
Visualization of RNA sequencing (RNA-Seq) data sets by t-distributed stochastic neighbor embedding (t-SNE) plot showed separation based on Lpin1 genotype, as well as separation between fasted and refed Lpin1–/– liver (Figure 1A)
Compared with the fed state, fasting in Lpin1+/+ liver led to altered expression of genes involved in cholesterol and amino acid metabolism, whereas in Lpin1–/– liver, fasting affected expression of mRNA processing, circadian entrainment, and various signaling pathway genes (Supplemental Figure 1A)
Summary
The regulation of lipid storage in mammalian tissues is critical for metabolic homeostasis. In addition to lipin 1 PAP activity, lipin 1 transits to the nucleus, where it influences the activity of several metabolic transcription factors. These include key regulators of fatty acid oxidation during fasting, such as PPARα and PPARγ coactivator 1α Lipin 1 in the nucleus leads to reduced levels of a key lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP1) [5]. Lipin proteins modulate cellular lipid homeostasis through the enzymatic conversion of lipid intermediates, as well as through interactions with transcription factors that regulate lipogenic and fatty acid oxidation gene expression
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