Lipin 1 modulates mRNA splicing during fasting adaptation in liver

JCI Insight. 2021 Sep 8;6(17):e150114. doi: 10.1172/jci.insight.150114.


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.

Keywords: Genetic diseases; Metabolism; Molecular biology; Mouse models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / genetics*
  • Alternative Splicing
  • Animals
  • Cells, Cultured
  • Fasting / physiology*
  • Female
  • Humans
  • Lipid Metabolism / genetics*
  • Liver / cytology
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Phosphatidate Phosphatase
  • RNA Splicing
  • RNA, Messenger / genetics*
  • Transcription Factors / genetics


  • RNA, Messenger
  • Transcription Factors
  • Lpin1 protein, mouse
  • Phosphatidate Phosphatase