StarD5 Plays a Critical Role in the Hepatocyte ER Stress Survival Response

The unfolded protein response (UPR) is a highly orchestrated survival response initiated in cells under endoplasmic reticulum (ER) stress. Steroidogenic acute regulatory-related lipid transfer domain 5 (StarD5) is an ER stress-responsive, cholesterol-binding protein under the regulation of IRE1. Based upon in vitro findings, StarD5 delivers a protective response by translocating ER cholesterol to the plasma membrane (PM) and accompanying protective changes in PM fluidity. The study aimed to determine if StarD5's ability to provide in vitro hepatocyte protective responses is translatable to in vivo conditions. ER stress in mouse livers was induced by intraperitoneal injection of tunicamycin (Tm). Adenovirus was used to restore the expression of StarD5 in the livers of StarD5^-/- mice. Immunoblotting, histological analysis, and lipid measurements were performed. Induction of ER stress led to increased expression of StarD5 and steatosis in the livers of wild-type (WT) mice, while in StarD5^-/- mice, steatosis and apoptosis were more acute compared to WT mice, as evidenced by increased lipid accumulation and cleavage of PARP, respectively. Selectively restoring StarD5 expression to ER-stressed StarD5^-/- mice blunted the effects of tunicamycin. StarD5 appears to play a critical role in the ER stress survival response through its ability to regulate intracellular cholesterol homeostasis.