Sustained endoplasmic reticulum (ER) stress plays a major role in the development of many
metabolic diseases, including
cardiovascular disease,
nonalcoholic fatty liver disease,
insulin resistance,
obesity, and diabetes. p32 is a multicompartmental
protein involved in the regulation of oxidative phosphorylation and
glucose oxidation. p32 ablation is associated with resistance to age-associated and diet-induced
obesity through a mechanism that remains largely unknown. Here, we show that p32 promotes
lipid biosynthesis by modulating
fatty acid-induced ER stress. We found that p32 interacts with endoplasmic reticulum-anchored
enzyme mannosyl-oligosaccharide glucosidase I (GCS1), an ER lumen-anchored
glucosidase that is essential for the processing of N-linked
glycoproteins, and reduces GCS1 in a lysosome-dependent manner. We demonstrate that increased GCS1 expression alleviates
fatty acid-induced ER stress and is critical for suppressing ER stress-associated lipogenic gene activation, as demonstrated by the down-regulation of Srebp1, Fasn, and Acc. Consistently, suppression of p32 leads to increased GCS1 expression and alleviates
fatty acid-induced ER stress, resulting in reduced
lipid accumulation. Thus, p32 and GCS1 are regulators of ER function and
lipid homeostasis and are potential therapeutic targets for the treatment of
obesity and diabetes.-Liu, Y., Leslie, P. L., Jin, A., Itahana, K., Graves, L. M., Zhang, Y. p32 regulates ER stress and
lipid homeostasis by down-regulating GCS1 expression.