Acyl-CoA:diacylglycerol acyltransferases (DGATs) catalyze the last step in triglyceride (TG) synthesis. The genes for two DGAT enzymes, DGAT1 and DGAT2, have been identified. To examine the roles of liver DGAT1 and DGAT2 in TG synthesis and very low density lipoprotein (VLDL) secretion, liver DGAT1-and DGAT2-overexpressing mice were created by adenovirus-mediated gene transfection. DGAT1-overexpressing mice had markedly increased DGAT activity in the presence of the permeabilizing agent alamethicin. This suggests that DGAT1 possesses latent DGAT activity on the lumen of the endoplasmic reticulum. DGAT1-overexpressing mice showed increased VLDL secretion, resulting in increased gonadal (epididymal or parametrial) fat mass but not subcutaneous fat mass. The VLDL-mediated increase in gonadal fat mass might be due to the 4-fold greater expression of the VLDL receptor protein in gonadal fat than in subcutaneous fat. DGAT2-overexpressing mice had increased liver TG content, but VLDL secretion was not affected. These results indicate that DGAT1 but not DGAT2 has a role in VLDL synthesis and that increased plasma VLDL concentrations may promote obesity, whereas increased DGAT2 activity has a role in steatosis.Triglyceride (TG) 1 is the major energy storage form and is synthesized primarily in three tissues: liver, adipose, and small intestine. In the liver, synthesized TG is either stored in cytoplasmic droplets or secreted as very low density lipoprotein (VLDL) particles. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is a membrane-bound enzyme that catalyzes the last step in the synthesis of TG. Classified by detergent sensitivity, two types of DGATs in microsomes have been proposed: the overt type (on the cytosol) catalyzes the synthesis of TG destined for cytoplasmic droplets, and latent type (on the lumen of the endoplasmic reticulum) catalyzes the synthesis of TG for VLDL formation (1). Because it has been well established that cytosolic droplet TG cannot be incorporated en bloc into VLDL (2), the relative activities of these two functions of DGAT may have a significant impact on the level of triglyceridemia as well as on the development of steatosis.Regarding the molecular aspects of DGAT, the cDNAs of DGATs, viz. DGAT1 and DGAT2, have been recently cloned and sequenced (3, 4). DGAT1 and DGAT2 are unrelated proteins that exhibit DGAT activity. DGAT1 is expressed ubiquitously, with the highest expression levels in the small intestine (3), and the phenotypes of DGAT1-null mice have been extensively examined (5-9). DGAT1-null mice are viable, can still synthesize TG, and have normal 4-h fasted plasma TG levels (5). These mice have reduced adiposity and are resistant to diet-induced obesity through a mechanism that involves increased energy expenditure (5). The increased energy expenditure is due partly to the increased peripheral leptin sensitivity in DGAT1-deficient mice (6). DGAT2 is expressed ubiquitously, with high expression levels in the liver and white adipose tissue (WAT) (4). In contrast to DGAT1-deficient ...
Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oilinduced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPAR␥) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. Conclusion: The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPAR␥.
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