Elongation of Long-Chain Fatty Acid Family Member 6 (Elovl6)-Driven Fatty Acid Metabolism Regulates Vascular Smooth Muscle Cell Phenotype Through AMP-Activated Protein Kinase/Krüppel-Like Factor 4 (AMPK/KLF4) Signaling.

BACKGROUND: Fatty acids constitute the critical components of cell structure and function, and dysregulation of fatty acid composition may exert diverging vascular effects including proliferation, migration, and differentiation of vascular smooth muscle cells (VSMCs). However, direct evidence for this hypothesis has been lacking. We investigated the role of elongation of long-chain fatty acid member 6 (Elovl6), a rate-limiting enzyme catalyzing the elongation of saturated and monounsaturated long-chain fatty acid, in the regulation of phenotypic switching of VSMC. METHODS AND RESULTS: Neointima formation following wire injury was markedly inhibited in Elovl6-null (Elovl6-/-) mice, and cultured VSMCs with siRNA-mediated knockdown of Elovl6 was barely responsive to PDGF-BB. Elovl6 inhibition induced cell cycle suppressors p53 and p21 and reduced the mammalian targets of rapamycin (mTOR) phosphorylation and VSMC marker expression. These changes are ascribed to increased palmitate levels and reduced oleate levels, changes that lead to reactive oxygen species (ROS) production and resulting AMP-activated protein kinase (AMPK) activation. Notably, Elovl6 inhibition robustly induced the pluripotency gene Krüppel-like factor 4 (KLF4) expression in VSMC, and KLF4 knockdown significantly attenuated AMPK-induced phenotypic switching of VSMC, indicating that KLF4 is a bona fide target of AMPK. CONCLUSIONS: We demonstrate for the first time that dysregulation of Elovl6-driven long-chain fatty acid metabolism induces phenotypic switching of VSMC via ROS production and AMPK/KLF4 signaling that leads to growth arrest and downregulation of VSMC marker expression. The modulation of Elovl6-mediated cellular processes may provide an intriguing approach for tackling atherosclerosis and postangioplasty restenosis.

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice.

Despite the established role of alveolar type II epithelial cells for the maintenance of pulmonary function, little is known about the deregulation of lipid composition in the pathogenesis of pulmonary fibrosis. The elongation of long-chain fatty acids family member 6 (Elovl6) is a rate-limiting enzyme catalysing the elongation of saturated and monounsaturated fatty acids. Here we show that Elovl6 expression is significantly downregulated after an intratracheal instillation of bleomycin (BLM) and in human lung with idiopathic pulmonary fibrosis. Elovl6-deficient (Elovl6⁻/⁻) mice treated with BLM exhibit severe fibroproliferative response and derangement of fatty acid profile compared with wild-type mice. Furthermore, Elovl6 knockdown induces a change in fatty acid composition similar to that in Elovl6⁻/⁻ mice, resulting in induction of apoptosis, TGF-ß1 expression and reactive oxygen species generation. Our findings demonstrate a previously unappreciated role for Elovl6 in the regulation of lung homeostasis, and in pathogenesis and exacerbation of BLM-induced pulmonary fibrosis.