ATGL/CGI-58-Dependent Hydrolysis of a Lipid Storage Pool in Murine Enterocytes

Abstract

Summary: As circulating lipid levels are balanced by the rate of lipoprotein release and clearance from the plasma, lipid absorption in the small intestine critically contributes to the maintenance of whole-body lipid homeostasis. Within enterocytes, excessive triglycerides are transiently stored as cytosolic lipid droplets (cLDs), and their mobilization sustains lipid supply during interprandial periods. Using mice lacking adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) exclusively in the intestine (intestine-specific double KO [iDKO]), we show that ATGL/CGI-58 are not involved in providing substrates for chylomicron synthesis. Massive intestinal cLD accumulation in iDKO mice independent of dietary lipids together with inefficient lipid incorporation into cLDs in the early absorption phase demonstrate the existence of a secretion/re-uptake cycle, corroborating the availability of two diverse cLD pools. This study identified ATGL/CGI-58 as critical players in the catabolism of basolaterally (blood) derived lipids and highlights the necessity to modify the current model of intestinal lipid metabolism. : Korbelius et al. demonstrate that the major enzyme for neutral lipolysis (ATGL) and its coactivator (CGI-58) are critically involved in intestinal lipid turnover. Circulating lipids accumulate in enterocytes of ATGL/CGI-58-deficient mice, whereas dietary lipids elude lipolysis by ATGL/CGI-58 during early absorption, substantiating the presence of a secretion and re-uptake cycle in enterocytes. Keywords: ATGL, CGI-58, small intestine, lipid droplets, lipid absorption, lipolysis, triacylglycerol, triglyceride