Lipin 1 modulates mRNA splicing during fasting adaptation in liver.
Huan Wang; Tracey W Chan; Ajay A Vashisht; Brian G Drew; Anna C Calkin; Thurl E Harris; James A Wohlschlegel; Xinshu Xiao; Karen Reue
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.
| Journal | JCI INSIGHT |
| ISSN | 2379-3708 |
| Published | 08 Sep 2021 |
| Volume | 6 |
| Issue | 17 |
| Pages | |
| DOI | 10.1172/jci.insight.150114 |
| Type | Journal Article |
| Sponsorship |