The Enzymes of Neutral Lipid Synthesis

Buhman, Kimberly K.; Chen, Hubert C.; Farese, Robert V.

doi:10.1074/jbc.r100050200

Cited by 149 publications

(119 citation statements)

References 73 publications

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“…The issue of which cell types contain ACAT1 and ACAT2 in the livers of experimental primates has not been questioned, and a similar pattern appears to be found in mice as well (23,24). Controversy exists with regard to whether the cellular distribution pattern in these two animals was also seen in human liver.…”

Section: Resultsmentioning

confidence: 96%

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Rudel

Davis

Sawyer

et al. 2002

Journal of Biological Chemistry

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The role of liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2), earlier shown to be the principal ACAT enzyme within primate hepatocytes, as a regulator of the hypercholesterolemia induced by dietary cholesterol was studied. At the end of low and high cholesterol diet periods, liver biopsies were taken from cynomolgus monkeys, a species highly responsive to dietary cholesterol, and less responsive African green monkeys. Liver cholesterol and cholesteryl ester concentrations were highest in cynomolgus monkeys fed cholesterol, despite the fact that in order to induce equivalent hypercholesterolemia, dietary cholesterol levels were 50% lower than was fed to green monkeys. Hepatic cholesteryl oleate secretion rate, measured during liver perfusion as an indicator of ACAT activity, was significantly higher in cynomolgus monkeys. Liver microsomal ACAT activity was 2-3-fold higher in cynomolgus monkeys than in green monkeys. The responses of ACAT2 were compared with those of ACAT1 that is found primarily in Kupffer cells. ACAT2 protein mass was significantly correlated to microsomal total ACAT activity in both species; ACAT1 mass was less well correlated. Dietary cholesterol induced a significant 3-fold increase of ACAT2 protein mass in cynomolgus monkeys, a much greater increase than was found for mRNA abundance; neither ACAT2 mRNA nor protein was diet-responsive in green monkeys. In cynomolgus monkeys but not in green monkeys, liver free cholesterol concentrations were elevated when cholesterol was fed and were correlated with ACAT2 protein levels. The data suggest a mechanism whereby the elevation of hepatic free cholesterol concentrations by dietary cholesterol, seen only in cynomolgus monkeys, resulted in higher ACAT2 protein levels in hepatocytes, either through increased production or stabilization of the protein. Regulation of ACAT2 gene transcription was not a factor.

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Section: Resultsmentioning

confidence: 96%

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Rudel

Davis

Sawyer

et al. 2002

Journal of Biological Chemistry

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“…The genes encoding these two enzymes have no sequence homology and they each belong to distinct gene families. DGAT1 belongs to a large family of membrane-bound O-acyltransferases that includes acyl-CoA: cholesterol acyltransferase (ACAT)-1 and -2, which catalyze cholesterol ester biosynthesis (5)(6)(7)(8)(9). DGAT2 belongs to the DGAT2/acyl-CoA:monoacylglycerol acyltransferase gene family that includes monoacylglycerol acyl-CoA acyltransferases 1-3 and wax synthase (3, 8, 10 -14).…”

Section: Triacylglycerols (Tg)mentioning

confidence: 99%

Murine Diacylglycerol Acyltransferase-2 (DGAT2) Can Catalyze Triacylglycerol Synthesis and Promote Lipid Droplet Formation Independent of Its Localization to the Endoplasmic Reticulum

McFie

Banman

Kary

et al. 2011

Journal of Biological Chemistry

130

114

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Triacylglycerol (TG) is the major form of stored energy in eukaryotic organisms and is synthesized by two distinct acylCoA:diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2. Both DGAT enzymes reside in the endoplasmic reticulum (ER), but DGAT2 also co-localizes with mitochondria and lipid droplets. In this report, we demonstrate that murine DGAT2 is part of a multimeric complex consisting of several DGAT2 subunits. We also identified the region of DGAT2 responsible for its localization to the ER. A DGAT2 mutant lacking both its transmembrane domains, although still associated with membranes, was absent from the ER and instead localized to mitochondria. Unexpectedly, this mutant was still active and capable of interacting with lipid droplets to promote TG storage. Additional experiments indicated that the ER targeting signal was present in the first transmembrane domain (TMD1) of DGAT2. When fused to a fluorescent reporter, TMD1, but not TMD2, was sufficient to target mCherry to the ER. Finally, the interaction of DGAT2 with lipid droplets was dependent on the C terminus of DGAT2. DGAT2 mutants, in which regions of the C terminus were either truncated or specific regions were deleted, failed to co-localize with lipid droplets when cells were oleate loaded to stimulate TG synthesis. Our findings demonstrate that DGAT2 is capable of catalyzing TG synthesis and promote its storage in cytosolic lipid droplets independent of its localization in the ER. Triacylglycerols (TG),2 the major form of stored energy in eukaryotic organisms, are synthesized via the multistep glycerol 3-phosphate or Kennedy pathway (1). In this pathway, three fatty acyl-coenzyme A (CoA) molecules (activated forms of fatty acids) are linked via ester bonds to a glycerol backbone. The microsomal enzyme, acyl-CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) catalyzes the final reaction of the pathway by forming an ester bond between a long chain fatty acid and the free hydroxyl group of diacylglycerol (DG) generating TG.Two different DGAT enzymes, DGAT1 and DGAT2, are responsible for the acyl-CoA-dependent synthesis of TG in mammalian tissues (2-4). The genes encoding these two enzymes have no sequence homology and they each belong to distinct gene families. DGAT1 belongs to a large family of membrane-bound O-acyltransferases that includes acyl-CoA: cholesterol acyltransferase (ACAT)-1 and -2, which catalyze cholesterol ester biosynthesis (5-9). DGAT2 belongs to the DGAT2/acyl-CoA:monoacylglycerol acyltransferase gene family that includes monoacylglycerol acyl-CoA acyltransferases 1-3 and wax synthase (3, 8, 10 -14). In mice and humans, DGAT1 and DGAT2 are expressed in most tissues, with the highest levels of expression found in tissues that are associated with TG metabolism (adipose tissue, liver, small intestine, and mammary gland) (3, 5).Studies in mice and in cells in culture have provided compelling evidence that DGAT2, more so than DGAT1, is responsible for the majority of TG synthesis and that these two enzymes have separa...

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“…This difference may be a result of a step in the ChE synthesis pathway; however, ACAT1 was not affected by the addition of n-3HUFAs. ACAT1 is an enzyme that binds acyl CoA and cholesterol to form ChE 29 . No significant difference was detected in free fatty acid synthesis, as illustrated in in Table 2; however, a non-significant difference in free fatty acid synthesis was actually observed, with the order of the n-3HUFAs, in terms of their level of reduction of free fatty acid synthesis, being THA DHA DPA EPA.…”

Section: Comparison Of Lipid-lowering Effect Among N-3hufasmentioning

confidence: 99%

A Comparison of the Lipid-lowering Effects of Four Different n-3 Highly Unsaturated Fatty Acids in HepG2 Cells

et al. 2014

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The Enzymes of Neutral Lipid Synthesis

Cited by 149 publications

References 73 publications

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Primates Highly Responsive to Dietary Cholesterol Up-regulate Hepatic ACAT2, and Less Responsive Primates Do Not

Murine Diacylglycerol Acyltransferase-2 (DGAT2) Can Catalyze Triacylglycerol Synthesis and Promote Lipid Droplet Formation Independent of Its Localization to the Endoplasmic Reticulum

A Comparison of the Lipid-lowering Effects of Four Different n-3 Highly Unsaturated Fatty Acids in HepG2 Cells

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