TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis

Abstract

Atherosclerosis, predominantly characterized by the disturbance of lipid homeostasis, has become the main causation of various cardiovascular diseases. Therefore, there is an urgent requirement to explore efficacious targets that act as lipid modulators for atherosclerosis. Transcription factor EB (TFEB), whose activity depends on post-translational modifications, such as phosphorylation, acetylation, SUMOylation, ubiquitination, etc., is significant for normal cell physiology. Recently, increasing evidence implicates a role of TFEB in lipid homeostasis, via its functionality of promoting lipid degradation and efflux through mediating lipophagy, lipolysis, and lipid metabolism-related genes. Furthermore, a regulatory effect on lipid transporters and lipid mediators by TFEB is emerging. Notably, TFEB makes a possible therapeutic target of atherosclerosis by regulating lipid metabolism. This review recapitulates the update and current advances on TFEB mediating lipid metabolism to focus on two intracellular activities: a) how cells perceive external stimuli and initiate transcription programs to modulate TFEB function, and b) how TFEB restores lipid homeostasis in the atherosclerotic process. In-depth research is warranted to develop potent agents against TFEB to alleviate or reverse the progression of atherosclerosis.

Keywords: TFEB; atherosclerosis; lipid homeostasis; lipid mediators; lipid transporters; lipophagy; post-translational modifications.

FIGURE 1

The structure and function of TFEB in lipid homeostasis. TFEB is a protein consisting of 476 amino acid residues, mainly including glutamine-rich (GIn rich), an acidic transcription activation domain (AD), basic helix-loop-helix leucine-zipper (bHLHZIP) structure, and proline-rich motifs (Pro rich). Phosphorylation and acetylation are the most important post-translational modifications to regulate TFEB activity. The phosphorylated or acetylated TFEB sites by different proteins are shown in the figure. TFEB is also regulated by transcription and non-coding RNA. MicroRNA-128 targets TFEB to tune the transcription of autophagy-related genes. Methyltransferase like 3 (METTL3) inhibits the transcriptional activity of TFEB by methylating two m⁶A residues. After being activated into the nucleus, TFEB regulates downstream autophagy-lysosomal genes to modulate lipophagy and neutral lipolysis. Furthermore, TFEB also regulates lipid transport processes such as lipid uptake and cholesterol efflux by CD36 and ATP-binding cassette transporter A1(ABCA1).