3/5/2023 0 Comments Sharemouse ip conflictCurrent interventions during acute episodes aim to alleviate symptoms through aggressive fluid and electrolyte replacement, shortened fasting periods, dietary regimens that restrict fat and/or increase carbohydrate intake, and monitoring for hyperkalemia and cardiac arrhythmias ( 12, 13, 15, 17). There is no treatment for lipin 1 deficiency. Notably, prolonged fasting is also a trigger for other genetic deficiencies that cause rhabdomyolytic disease, such as deficiencies in fatty acid oxidation enzymes ( 16). Disease episodes in lipin 1–deficient individuals are triggered by metabolic stressors such as fasting, extreme exercise, or fever ( 12– 15). Rhabdomyolytic bouts can be triggered in adults with lipin 1 deficiency, as well ( 12– 14). Lipin 1 deficiency causes recurrent episodes of rhabdomyolysis and myoglobinuria in children, with about a 10% mortality rate, likely promoted by acute kidney failure, cardiac arrhythmia, and hyperkalemia ( 8– 11). Lipin proteins are required for human health. Thus, 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. Lipin 1 nuclear translocation from the cytoplasm is regulated by several factors, including interaction with 14-3-3 proteins and sumoylation ( 6, 7). Lipin 1 in the nucleus also leads to reduced levels of a key lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP1) ( 5). Lipin 1 transcriptional coactivator activity appears not to require PAP function, but it does require a hydrophobic motif (LXXIL) located downstream of the PAP active site to mediate protein-protein interactions between lipin 1 and transcription factors ( 4). These include key regulators of fatty acid oxidation during fasting, such as PPARα and PPARγ coactivator 1α (PGC-1α ref. In addition to lipin 1 PAP activity, lipin 1 transits to the nucleus, where it influences the activity of several metabolic transcription factors. The lipin proteins (lipin 1, lipin 2, and lipin 3) perform a key reaction in the synthesis of triglycerides and phospholipids through their phosphatidate phosphatase (PAP) activity, which converts phosphatidic acid to diacylglycerol at the endoplasmic reticulum (ER) membrane ( 2, 3). Excessive or inadequate triglyceride storage is associated with insulin resistance, fatty liver disease, and dyslipidemia ( 1). The regulation of lipid storage in mammalian tissues is critical for metabolic homeostasis. 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. 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. 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. The role of lipin 1 in mRNA splicing was largely independent of its enzymatic function. We determined that lipin 1 deficiency induces widespread alternative mRNA splicing in liver during fasting, much of which is normalized by refeeding. We sought to identify critical lipin 1 activities during fasting. Lipin 1–deficient individuals exhibit episodic disease symptoms that are triggered by metabolic stress, such as stress caused by prolonged fasting. Lipin 1 regulates cellular lipid homeostasis through roles in glycerolipid synthesis (through phosphatidic acid phosphatase activity) and transcriptional coactivation.
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