Inhibitory activity of diacylglycerol acyltransferase by tanshinones from the root ofSalvia miltiorrhiza

Ko, Jeong Suk; Ryu, Shi Young; Kim, Young Sup; Chung, Mi Yeon; Kang, Jong Seong; Rho, Mun‐Chual; Lee, Hyun Sun; Kim, Young Kook

doi:10.1007/bf02976599

Cited by 33 publications

(16 citation statements)

References 9 publications

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“…151). Numerous agents have been reported to inhibit DGAT activity, including a variety of substances isolated from microorganisms (152)(153)(154)(155)(156) and fish oils (157), but it is unclear whether these agents inhibit one or both DGAT enzymes. Recently, a selective smallmolecule inhibitor of DGAT1 was reported to reduce weight gain and hepatic TG when administered to mice fed a high-fat diet (115).…”

Section: Dgat Inhibitorsmentioning

confidence: 99%

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Yen

Stone

Koliwad

et al. 2008

Journal of Lipid Research

935

782

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Triacylglycerols (triglycerides) (TGs) are the major storage molecules of metabolic energy and FAs in most living organisms. Excessive accumulation of TGs, however, is associated with human diseases, such as obesity, diabetes mellitus, and steatohepatitis. The final and the only committed step in the biosynthesis of TGs is catalyzed by acylCoA:diacylglycerol acyltransferase (DGAT) enzymes. The genes encoding two DGAT enzymes, DGAT1 and DGAT2, were identified in the past decade, and the use of molecular tools, including mice deficient in either enzyme, has shed light on their functions. Although DGAT enzymes are involved in TG synthesis, they have distinct protein sequences and differ in their biochemical, cellular, and physiological functions. Both enzymes may be useful as therapeutic targets for diseases. Here we review the current knowledge of DGAT enzymes, focusing on new advances since the cloning of their genes, including possible roles in human health and diseases.-Yen, C-L. E., S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese, Jr. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 2008. 49: 2283-2301. Supplementary key words triacylglycerolsTriacylglycerols (triglycerides) (TGs), a major type of neutral lipid, are a heterogeneous group of molecules with a glycerol backbone and three FAs attached by ester bonds. The physical and chemical properties of TG differ based on chain length and the degree to which their FAs are desaturated. TGs serve multiple important functions in living organisms. Chief among these, they are the major storage molecules of FA for energy utilization and the synthesis of membrane lipids. Because they are highly reduced and anhydrous, TGs store 6-fold more energy than the same amount of hydrated glycogen (1). In plants, TGs are a major component of seed oils, which are valuable resources for dietary consumption and industrial uses. TG from plants and microorganisms can also be used for biofuels. In animals, energy stores of TG are concentrated primarily in adipocytes, although TGs are also found prominently in myocytes, hepatocytes, enterocytes, and mammary epithelial cells. In addition to energy storage, TG synthesis in cells may protect them from the potentially toxic effects of excess FA. In the enterocytes and hepatocytes of most mammals, TGs are synthesized for the assembly and secretion of lipoproteins, which transport dietary and endogenously synthesized FA between tissues. Also, TGs in secreted lipids acts as a component of the skinʼs surface water barrier, and collections of TG in adipose tissue provide insulation for organisms.Although TGs are essential for normal physiology, the excessive accumulation of TG in human adipose tissue results in obesity and, in nonadipose tissues, is associated with organ dysfunction. For example, excessive TG deposition in skeletal muscle and the liver is associated with insulin resistance, in the liver with nonalcoholic steatohepatitis, and in the heart with cardiomyopathy (2, 3). Owing to worldwide increases in the p...

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Section: Dgat Inhibitorsmentioning

confidence: 99%

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Yen

Stone

Koliwad

et al. 2008

Journal of Lipid Research

935

782

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“…Although there are no available synthetic inhibitors of DGAT1, several naturally occurring compounds have been reported to inhibit DGAT activity in vitro. [23][24][25][26][27][28] To date, no studies to our knowledge have reported the effects of these DGAT inhibitors on energy and glucose metabolism in animal models. It is also unclear whether these compounds specifically inhibit DGAT1 or also antagonize the activities of DGAT2.…”

Section: From Mice To Humans: Clinical and Pharmaceutical Implicationsmentioning

confidence: 99%

Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity

Chen

Farese

2005

ATVB

160

115

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Abstract-Because the ability to make triglycerides is essential for the accumulation of adipose tissue, inhibition of triglyceride synthesis may ameliorate obesity and its related medical consequences. Acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) is 1 of 2 DGAT enzymes that catalyze the final reaction in the known pathways of mammalian triglyceride synthesis. Mice lacking DGAT1 are resistant to obesity and have increased sensitivity to insulin and leptin. DGAT1-deficient mice are also resistant to diet-induced hepatic steatosis. The effects of DGAT1 deficiency on energy and glucose metabolism result in part from the altered secretion of adipocyte-derived factors. Although complete DGAT1 deficiency causes alopecia and impairs development of the mammary gland, these abnormalities are not observed in mice with partial DGAT1 deficiency. These findings suggest that pharmacological inhibition of DGAT1 may be a feasible therapeutic strategy for human obesity and type 2 diabetes. O besity can be viewed as an energy balance disorder, arising when energy input exceeds energy output, with most of the excess calories converted into triglycerides and stored in the adipose tissue. Medications currently approved for the treatment of obesity attempt to restore energy balance primarily by decreasing energy input-by either suppressing appetite or interfering with lipid absorption in the small intestine. Because of the rapid increase in the prevalence of obesity worldwide and the lack of efficacy of current medical therapies, 1 efforts to develop novel pharmacological therapies for obesity have intensified.One potential therapeutic strategy involves inhibiting triglyceride synthesis. Although triglycerides are essential for normal physiology, excess triglyceride accumulation results in obesity and, particularly when it occurs in nonadipose tissues, is associated with insulin resistance. However, until recently it had been unclear whether disrupting triglyceride synthesis would be feasible or would instead cause significant adverse consequences. In the past several years, pharmacological inhibition of acyl coenzyme A (CoA):diacylglycerol acyltransferase 1 (DGAT1) has emerged as a potential strategy for inhibiting triglyceride synthesis. Here, we review recent findings from studies of mice lacking DGAT1 that are pertinent to the prospects of DGAT1 as a pharmaceutical target. DGAT Enzymes and Triglyceride SynthesisThe cloning of genes encoding DGAT enzymes provided important molecular tools to examine the relationship between triglyceride synthesis and obesity. The DGAT1 gene was identified from its homology to acyl CoA:cholesterol acyltransferase genes 2,3 and was shown to encode an enzyme with DGAT activity. 2 The DGAT2 gene was identified byOriginal

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“…The flavonoids inhibited DGAT activity in a dose-dependent manner with IC 50 values of 10.9 mM (1), 9.8 mM (2), 8.6 mM (3), 142.0 mM (4) and 250 mM (5). The prenylflavonoids without C3-OH (1,2,3) showed stronger inhibition than those with C3-OH (4,5). On the other hand, flavonoids without side chains (hesperetin, naringenin, quercetin and kaempferol) did not inhibit the enzyme activity at a final concentration of 800 mM.…”

Section: Introductionmentioning

confidence: 91%

“…Four prenylflavonoids, kurarinone (1), a chalcone of 1, kuraridin (2), kurarinol (3), kushenol H (4) and kushenol K (5) isolated from the roots of Sophora flavescens were investigated for their inhibitory effects on diacylglycerol acyltransferase (DGAT). The flavonoids inhibited DGAT activity in a dose-dependent manner with IC 50 values of 10.9 mM (1), 9.8 mM (2), 8.6 mM (3), 142.0 mM (4) and 250 mM (5).…”

Section: Introductionmentioning

confidence: 99%

In vitroInhibition of Diacylglycerol Acyltransferase by Prenylflavonoids fromSophora flavescens

Chung

Rho²,

Ko³

et al. 2004

Planta med

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Four prenylflavonoids, kurarinone ( 1), a chalcone of 1, kuraridin ( 2), kurarinol ( 3), kushenol H ( 4) and kushenol K ( 5) isolated from the roots of Sophora flavescens were investigated for their inhibitory effects on diacylglycerol acyltransferase (DGAT). The flavonoids inhibited DGAT activity in a dose-dependent manner with IC50 values of 10.9 microM ( 1), 9.8 microM ( 2), 8.6 microM ( 3), 142.0 microM ( 4) and 250 microM ( 5). The prenylflavonoids without C3-OH ( 1, 2, 3) showed stronger inhibition than those with C3-OH ( 4, 5). On the other hand, flavonoids without side chains (hesperetin, naringenin, quercetin and kaempferol) did not inhibit the enzyme activity at a final concentration of 800 microM. These data suggest that the lavandulyl side chain and the position of the hydroxy group are important for high DGAT inhibitory activity. Compound 1 also inhibited de novo synthesis of triacylglycerol (TG) in Raji cells.

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Inhibitory activity of diacylglycerol acyltransferase by tanshinones from the root ofSalvia miltiorrhiza

Cited by 33 publications

References 9 publications

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis

Inhibition of Triglyceride Synthesis as a Treatment Strategy for Obesity

In vitroInhibition of Diacylglycerol Acyltransferase by Prenylflavonoids fromSophora flavescens

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