Hepatic VLDL secretion: DGAT1 determines particle size but not particle number, which can be supported entirely by DGAT2

Abstract

We investigated whether, in view of its activity being expressed on both aspects of the endoplasmic reticulum (ER; dual membrane topology), diacylglycerol acyltransferase 1 (DGAT1) plays a distinctive role in determining the triglyceride (TAG) content of VLDL particles secreted by the liver. Mice in which the DGAT1 gene was specifically ablated in hepatocytes (DGAT1-LKO mice) had the same number of VLDL particles (apoB concentration) in the plasma 1 h after Triton 1339 treatment, but these particles were approximately half the size of VLDL particles secreted by control mice and had a proportionately decreased content of TAG, with normal cholesterol and cholesteryl ester contents. Analyses of purified microsomal fractions prepared from 16 h fasted control and DAGT1-LKO mice showed that the TAG/protein ratio in the ER was significantly lower in the latter. Electron micrographs of these livers showed that those from DGAT1-LKO mice did not show the increased lipid content of the smooth ER shown by control livers. The effects of DGAT1- and DGAT2-specific inhibitors on apoB secretion by HepG2 cells showed that DGAT1 is not indispensable for apoB secretion and demonstrated redundancy in the ability of the two enzymes to support apoB secretion. Therefore, our findings show that DGAT1 is essential for the complete lipidation and maturation of VLDL particles within the lumen of the ER, consistent with its dual topology within the ER membrane. In the mouse, DGAT2 can support apoB secretion (particle number) even when TAG availability for full VLDL lipidation is restricted in the absence of DGAT1.

Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S‐sulfhydration

“…In contrast, DGAT2 is localized in the ER and around LDs and is specialized in LDs. 44 Our data demonstrated that the expression of DGAT1 and 2 was significantly increased in hearts of db/db mice. Some studies have confirmed that LDs increased in abundance where UPR is activated.…”

Fatty Acids Inhibit LAMP2-Mediated Autophagy Flux via Activating ER Stress Pathway in Alcohol-Related Liver Disease

“…It has been reported that DGAT1 participates in VLDL secretion, with one study showing that DGAT1 overexpression in mouse liver increased VLDL secretion 39 and the other showing that DGAT1 is involved in lipidation and maturation of hepatic VLDL particles. 32 Our fast protein liquid chromatography and immunoblot analysis results suggest that DGAT1 may be involved in VLDL lipidation and secretion because DGAT1 deletion resulted in a decrease of serum VLDL-TG levels as well as ApoB100 protein levels after alcohol feeding. Thus, DGAT1-mediated VLDL secretion of TG is an adaptive response to the increased exogenous FFAs influx to the liver.…”

Intestine-specific DGAT1 deficiency improves atherosclerosis in apolipoprotein E knockout mice by reducing systemic cholesterol burden

“…Thus, directing TG as Mttp substrate away from lumenal LDs may reduce Mttp transcription and, consequently, influence the expression of cholesterol transporters. VLDL particle size was also reduced in hepatocyte-specific Dgat1 −/− mice [ 34 ], indicating that Dgat1 is critical for the size of ApoB-containing lipoproteins. Unaltered cholesterol content in VLDL of these mice is in line with differently regulated cholesterol incorporation into ApoB-containing lipoproteins of hepatocytes and enterocytes, since in enterocytes this process is largely dependent on TG incorporation into CMs [ 29 ].…”