Grasp55−/− mice display impaired fat absorption and resistance to high-fat diet-induced obesity

Abstract

The Golgi apparatus plays a central role in the intracellular transport of macromolecules. However, molecular mechanisms of Golgi-mediated lipid transport remain poorly understood. Here, we show that genetic inactivation of the Golgi-resident protein GRASP55 in mice reduces whole-body fat mass via impaired intestinal fat absorption and evokes resistance to high-fat diet induced body weight gain. Mechanistic analyses reveal that GRASP55 participates in the Golgi-mediated lipid droplet (LD) targeting of some LD-associated lipases, such as ATGL and MGL, which is required for sustained lipid supply for chylomicron assembly and secretion. Consequently, GRASP55 deficiency leads to reduced chylomicron secretion and abnormally large LD formation in intestinal epithelial cells upon exogenous lipid challenge. Notably, deletion of dGrasp in Drosophila causes similar defects of lipid accumulation in the midgut. These results highlight the importance of the Golgi complex in cellular lipid regulation, which is evolutionary conserved, and uncover potential therapeutic targets for obesityassociated diseases.

Secretory autophagy machinery and vesicular trafficking are involved in HMGB1 secretion

“…C57BL/6 WT and gorasp2 −/- mice were used [ 70 ]. Mice were maintained under pathogen-free conditions and a 12:12 h light-dark cycle.…”

Protein Kinase D2 drives chylomicron‐mediated lipid transport in the intestine and promotes obesity

“…However, further studies will be needed to identify the precise mechanism of APOA4 regulation by PKD2. Alternatively, intestinal PKD2 may increase lipid absorption, chylomicron formation, and release as well as body weight through regulation of the stability/activity of lipid droplet‐destined proteins in the Golgi (Kim et al, 2020). We should also add that, while inhibition/deletion of PKD2 did not affect FA uptake at the apical side of Caco2 cell layer in the short‐term, it did lead to fattier stools in mice in the long term.…”

Role of Mcpip1 in obesity‐induced hepatic steatosis as determined by myeloid and liver‐specific conditional knockouts

“…Although we do not have experimental data to support this view, this kind of molecular mechanism has already been described. Recently, the genetic inactivation of the Golgi‐resident protein GRASP55 in mice was demonstrated to reduce whole‐body fat mass via impaired intestinal fat absorption, causing resistance to high‐fat diet‐induced body weight gain [53].…”