Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis

Area of Science:

• Biochemistry
• Cell Biology
• Pulmonology

Background:

• Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease primarily affecting women.
• LAM pathogenesis is linked to mutations in tuberous sclerosis complex (TSC) genes, impacting mTORC1 signaling.
• Dysregulated cellular metabolism is implicated in LAM, but specific lipid alterations remain unclear.

Purpose of the Study:

• To identify lipid alterations in LAM patients.
• To investigate the role of TSC2 deficiency in lysophosphatidylcholine (LPC) generation.
• To explore potential therapeutic strategies targeting lipid metabolism in LAM.

Main Methods:

• Plasma lipid profiling using mass spectrometry in LAM patients and controls.
• In vitro preclinical models of TSC/LAM with TSC2-deficient and control cells.
• Analysis of lipid species, including lysoglycerophospholipids and neutral lipids.
• Pharmacological inhibition of mTORC1 and SREBP, and phospholipase A2 isoforms.

Main Results:

• Elevated levels of four specific lysophosphatidylcholine (LPC) species were found in LAM patients' plasma.
• TSC2-deficient cells exhibited significant LPC accumulation compared to TSC2-expressing cells.
• Rapamycin, torin1, or SREBP downregulation did not reduce LPC in TSC2-deficient cells.
• Inhibition of phospholipase A2 isoforms reduced the proliferation of TSC2-deficient cells.

Conclusions:

• TSC2-deficient cells demonstrate enhanced choline phospholipid metabolism.
• The TSC proteins play a novel role in regulating choline lysoglycerophospholipid metabolism.
• These findings suggest new therapeutic avenues for LAM targeting lipid metabolism.