Mechanisms of scramblases in regulating hepatic lipoprotein secretion and autophagy

Lipoprotein secretion is a complex, highly regulated multi-step process that ensures the efficient transport of lipids from cells into the bloodstream, supporting overall metabolic health. The secretion of very-low-density lipoprotein (VLDL) relies on the proper assembly and movement of phospholipids within cellular membranes, particularly the endoplasmic reticulum (ER). Changes in the composition and dynamics of phospholipids can affect lipoprotein size, lipid loading, and, ultimately, the ability of VLDL to be secreted. Scramblases are a class of transmembrane proteins that facilitate the movement of phospholipids between the inner and outer leaflets of membrane bilayers in a bidirectional, energy-independent manner, serving an equilibrating function. They help balance phospholipids to reduce mechanical strain and curvature in membranes, which is critical for various cellular processes, including autophagy. Recent evidence suggests that the scramblases TMEM41B and VMP1 play essential roles in regulating VLDL secretion. Loss of hepatic TMEM41B or VMP1 results in severe defects in VLDL secretion and leads to the rapid development of metabolic dysfunction-associated steatohepatitis (MASH) in mice. In this review, we discuss the latest advancements in understanding these lipid scramblases, highlighting their similarities and distinct roles in maintaining lipid homeostasis, membrane dynamics, autophagy, and VLDL secretion in the pathogenesis of MASH.