ライフサイエンスコーパス: ATGL

1 ATGL and HSL are robustly expressed by adipocytes that w

2 ATGL could constitute a new therapeutic strategy to targ

3 ATGL gene mutations cause a severe phenotype especially

4 ected small hairpin RNAs demonstrate that 1) ATGL activity is required for all PKA-stimulated FA and

5 nabled ABHD4 (ABHD4 N303R/S332G) to activate ATGL in Cos7 cells, brown adipocytes, and artificial lip

6 1 restrain the ability of CGI-58 to activate ATGL under basal conditions.

7 In addition, ATGL mediates the effects of beta-adrenergic signaling o

8 tively disrupted lipolysis without affecting ATGL lipid droplet translocation or ABHD5 interactions w

9 ctivity of the HCV core protein with altered ATGL binding to CGI-58 and the enhanced association of b

10 Although ATGL deficiency is compatible with normal skin developme

11 Although ATGL gain and loss of function did not alter hepatic TAG

12 he proliferation and invasion, suggesting an ATGL-independent role of ABHD5 in modulating PCa aggress

13 ells expressing both ectopic perilipin 5 and ATGL showed a 3-fold increase in lipolysis following act

14 muscle lipolysis depends on both CGI-58 and ATGL.

15 ts a direct functional role for both HSL and ATGL in hepatic lipid homeostasis and identifies these e

16 ed 3-5 days after infection in both HSL- and ATGL-overexpressing male mice, suggesting an increase in

17 palmitoyltransferase 1 alpha) in both WT and ATGL KO mice.

18 Wild-type (WT) and ATGL knockout (KO) mice were challenged with tunicamycin

19 Because ATGL preferentially generates sn-1,3 and sn-2,3, it sugg

20 xpectedly, increased the interaction between ATGL and its activator CGI-58 as well as the recruitment

21 late an epidermal triglyceride lipase beyond ATGL required for the adequate provision of fatty acids

22 ased by ATGL overexpression and decreased by ATGL knockdown.

23 etion, fatty acid oxidation was increased by ATGL overexpression and decreased by ATGL knockdown.

24 cetylase activity is positively regulated by ATGL to promote PGC-1alpha signaling.

25 n) murine models of type 1 diabetes, cardiac ATGL protein expression and TAG content were significant

26 shows that after diabetes, increased cardiac ATGL expression is an adaptive, albeit insufficient, res

27 xamined whether alterations in cardiomyocyte ATGL impact cardiac function during uncontrolled type 1

28 hepatic phenotype in MCD- or LPS-challenged ATGL-knockout (KO) mice.

29 diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiat

30 Consequently, ATGL knockdown reduced maximal oxidation of fatty acids,

31 and the expression of Egr1 while decreasing ATGL levels in epididymal fat.

32 K-ASKO ablation show no changes in desnutrin/ATGL levels but have defective phosphorylation of desnut

33 es have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte l

34 lipase A(2) (PLA(2))zeta and mouse desnutrin/ATGL) has been described in adipose cells as a member of

35 phosphorylation and regulation of desnutrin/ATGL and HSL and thus adipose lipolysis.

36 have defective phosphorylation of desnutrin/ATGL at S406 to decrease its triacylglycerol (TAG) hydro

37 hat the evolutionarily conserved mTORC1-Egr1-ATGL regulatory pathway represents an important componen

38 nd regulates its interaction with endogenous ATGL promotors.

39 odel that core reduces lipolysis by engaging ATGL.

40 s redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis.

41 We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumve

42 MCD-fed ATGL-KO mice, although partially protected from peripher

43 Mutations in the genes coding for ATGL or CGI-58 in humans cause neutral lipid storage dis

44 or CGI-58, indicating a predominant role for ATGL.

45 This peptide is highly selective for ATGL and does not inhibit other lipases, including hormo

46 In embryonic fibroblasts derived from ATGL KO mice, exogenous free fatty acids did not affect

47 been presumed that fatty acids derived from ATGL-catalyzed lipolysis act as PPAR-alpha ligands.

48 results demonstrate a crucial role for FSP27-ATGL interactions in regulating lipolysis, triglyceride

49 Knocking down hepatic ATGL completely abrogated the increase in serum insulin

50 Hence, we tested the contribution of hepatic ATGL on mediating glucose tolerance and insulin action.

51 Adenovirus-mediated knockdown of hepatic ATGL resulted in steatosis in mice and decreased hydroly

52 target genes in mice with suppressed hepatic ATGL expression.

53 Mice with suppressed hepatic ATGL had reduced hepatic glucose production in vivo, and

54 en together, these data suggest that hepatic ATGL knockdown enhances glucose tolerance by increasing

55 reptozotocin-diabetic mice with heterozygous ATGL deficiency and cardiomyocyte-specific ATGL overexpr

56 reptozotocin-diabetic mice with heterozygous ATGL deficiency displayed increased TAG accumulation, li

57 fully capable of inhibiting mouse and human ATGL.

58 In humans, ATGL deficiency causes neutral lipid storage disease wit

59 In addition to altering TAG hydrolysis, ATGL was shown to play a significant role in partitionin

60 TM increased hepatic TG accumulation in ATGL KO, but not in WT, mice.

61 The marked increase in ATGL protein levels in cardiac muscle of CGI-58KOM mice

62 down-regulated by TM in WT and even more in ATGL KO mice, which displayed strongly reduced serum VLD

63 hanges in PAT composition but also increased ATGL, suggesting a relative PAT deficiency.

64 dentification-58 (CGI-58) strongly increased ATGL-mediated TG catabolism in cell culture experiments.

65 xidative metabolism in response to increased ATGL-mediated lipolysis.

66 To determine whether increased ATGL expression during diabetes is detrimental or benefi

67 sts with FoxO1-encoding lentivirus increases ATGL expression and renders it sensitive to regulation b

68 down of Egr1 in 4E-BP1/2-null MEFs increases ATGL expression and decreases fat storage.

69 oth PKA activation and isoproterenol-induced ATGL translocation to the LD periphery.

70 Thus, by inhibiting ATGL, HIG2 acts downstream of HIF-1 to sequester FAs in

71 eptide corresponding to this region inhibits ATGL in a noncompetitive manner in the nanomolar range.

72 lates, but forced expression of SRA inhibits ATGL expression and free fatty acids (FFA) beta-oxidatio

73 SRA inhibits ATGL promoter activity, primarily by inhibiting the othe

74 Mice lacking ATGL or hormone-sensitive lipase (HSL) were challenged w

75 ts in adipose tissue, compatible with latent ATGL stimulation.

76 we show that 4E-BP1/2-null MEFs express less ATGL and accumulate more fat than control cells, while k

77 We provide an alternate mechanism that links ATGL to PPAR-alpha signaling.

78 ysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty

79 t loss via the adipocyte triglyceride lipase ATGL-1.

80 he discovery of adipose triglyceride lipase (ATGL) and comparative gene identification-58 (CGI-58) as

81 polytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL).

82 udies show that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) act sequentiall

83 d the role that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) plays in the in

84 tosolic lipases adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL).

85 Adipose triglyceride lipase (ATGL) and its coactivator comparative gene identificatio

86 have identified adipose triglyceride lipase (ATGL) as a major lipase in adipose tissue, although its

87 with increased adipose triglyceride lipase (ATGL) at the LD surface.

88 rol hydrolysis, adipose triglyceride lipase (ATGL) has been proposed to influence the storage/product

89 have shown that adipose triglyceride lipase (ATGL) increases the activity of the nuclear receptor PPA

90 Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) cataboli

91 Adipose triglyceride lipase (ATGL) is rate-limiting for the initial step of triacylgl

92 Adipose triglyceride lipase (ATGL) is the predominant triacylglycerol (TAG) hydrolase

93 otein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase w

94 In liver, adipose triglyceride lipase (ATGL) serves as a major triacylglycerol (TAG) lipase and

95 unaffected, and adipose triglyceride lipase (ATGL) was suppressed.

96 us inhibitor of adipose triglyceride lipase (ATGL), a key enzyme in intracellular lipolysis.

97 lipolysis by adipocyte triglyceride lipase (ATGL), a key lipase in adipocytes and non-adipose cells.

98 an inhibitor of adipose triglyceride lipase (ATGL), a key mediator of intracellular triacylglycerol (

99 vels of SRA and adipose triglyceride lipase (ATGL), a major hepatic triacylglycerol (TAG) hydrolase,

100 degradation of adipose triglyceride lipase (ATGL), a rate limiting enzyme of TAG hydrolysis.

101 by attenuating adipose triglyceride lipase (ATGL), but repression of oncogene-induced transformation

102 polytic enzyme, adipose triglyceride lipase (ATGL), has two FoxO1-binding sites, and co-transfection

103 e expression of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), lipolysis, lipoge

104 l TAG hydrolase adipose triglyceride lipase (ATGL), in the regulation of cardiac lipolysis.

105 TAG hydrolase, adipose triglyceride lipase (ATGL), regulates baseline cardiac metabolism and functio

106 tive lipase and adipose triglyceride lipase (ATGL), suggesting a link between adipocyte oxygen sensin

107 ism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis.

108 the activity of adipose triglyceride lipase (ATGL), the key lipolytic enzyme in the first step of TG

109 express neither adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triglyceride catabol

110 the activity of adipose triglyceride lipase (ATGL), the rate-limiting enzyme in triacylglycerol hydro

111 ipase (HSL) and adipose triglyceride lipase (ATGL), two enzymes critical for lipolysis in adipose tis

112 tic activity of adipose triglyceride lipase (ATGL), which catalyzes the hydrolysis of TGs to diacylgl

113 ed regulator of adipose triglyceride lipase (ATGL)-mediated lipolysis that plays important roles in m

114 n increase in adipocyte triglyceride lipase (ATGL)-mediated triglyceride breakdown and prolongation o

115 tic activity of adipose triglyceride lipase (ATGL).

116 olonged drop in adipose triglyceride lipase (ATGL).

117 nteracting with adipose triglyceride lipase (ATGL, also called desnutrin or PNPLA2).

118 affect adipose or liver triglyceride lipase (ATGL, known also as Pnpla2) mRNA in Pnpla3(+/+) and Pnpl

119 Since adipose triglyceride lipase (ATGL/PNPLA2) is the key enzyme for intracellular hydroly

120 the absence of adipose triglyceride lipase (ATGL/PNPLA2)-the main enzyme for intracellular lipolysis

121 in (also called adipose triglyceride lipase [ATGL]) in adipocytes (aP2-desnutrin) and also performed

122 ranscription of adipose triglyceride lipase, ATGL.

123 he de novo lipogenic program and the lipases ATGL and HSL.

124 fasting in mice, and the expression of liver ATGL was induced by SRAKO under normal and high fat diet

125 contrast, myosin heavy chain promoter (MHC)-ATGL mice were resistant to diabetes-induced increases i

126 Moreover, hearts from diabetic MHC-ATGL mice exhibited decreased reliance on palmitate oxid

127 Moreover, ATGL-KO mice challenged by LPS showed enhanced hepatic i

128 into perilipin 5 by 2-fold, whereas neither ATGL nor CGI-58 was labeled under the incubation conditi

129 nduced exclusively in TM-treated WT, but not ATGL KO, mice.

130 Our studies establish perilipin 5 as a novel ATGL partner and provide evidence that the protein compo

131 hese effects were reversed by co-ablation of ATGL.

132 prevent excessive obesity in the absence of ATGL.

133 ulates lipolysis primarily via activation of ATGL expression.

134 s and mobilizes CGI-58 for the activation of ATGL.

135 ion to LDs and CGI-58-mediated activation of ATGL.

136 drolase domain containing-5, an activator of ATGL, and negatively with mRNA levels of lipid droplet p

137 e LD surface regulates lipolytic activity of ATGL.

138 The compatibility of ATGL deficiency with normal epidermal function indicated

139 Thus, we tested the contribution of ATGL to hepatic lipid metabolism and signaling.

140 ucing LD growth and enhancing degradation of ATGL.

141 Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues.

142 r, reducing lipolysis by either depletion of ATGL or expression of exogenous full-length FSP27 or ami

143 onism was unable to normalize the effects of ATGL knockdown on PPAR-alpha target gene expression, and

144 als; however, the tissue-specific effects of ATGL outside of adipose tissue have not been well charac

145 T3-L1 adipocytes decreases the expression of ATGL and attenuates basal and isoproterenol-stimulated l

146 ic expression of Rheb inhibits expression of ATGL and HSL at the level of transcription, suppresses l

147 in human adipocytes increases expression of ATGL at the level of transcription, whereas overexpressi

148 the ATGL promoter in vitro and expression of ATGL in cultured adipocytes.

149 Co-expression of ATGL reverses the changes in LD phenotype induced by LDA

150 While expression of ATGL, HSL and CGI-58 remains mostly unaffected, TNF-alph

151 adipocytes by controlling the expression of ATGL.

152 in livers or mouse embryonic fibroblasts of ATGL(-/-) mice no longer decreases TG degradation as obs

153 ed transformation by G0S2 was independent of ATGL inhibition.

154 nt of metabolic disorders, the inhibition of ATGL by G0S2-derived peptides may represent a novel ther

155 Pharmacological inhibition of ATGL enzyme activity similarly reduced triglyceride-hydr

156 Pharmacological inhibition of ATGL may prove useful to prevent HFD-induced obesity and

157 HIG2), a HIF-1 target, as a new inhibitor of ATGL.

158 e, but with opposite effects; interaction of ATGL with CGI-58 increased lipolysis, whereas interactio

159 increased lipolysis, whereas interaction of ATGL with perilipin 5 decreased lipolysis.

160 l culture model, we examined interactions of ATGL and its co-lipase CGI-58 with perilipin 1 (perilipi

161 rmed in Hepa1.6 cells after the knockdown of ATGL before FA and TM treatment.

162 Knockdown of ATGL reduced cAMP-mediated induction of genes involved i

163 Interestingly, knockdown of ATGL, the best-known molecular target of ABHD5, impeded

164 in brown adipocytes with stable knockdown of ATGL.

165 Lack of ATGL may protect from hepatic ER stress through alterati

166 both chow and high-fat diets, modulation of ATGL-mediated IMTG hydrolysis did not significantly infl

167 as RFWD2) binds to the consensus VP motif of ATGL and targets it for proteasomal degradation by K-48

168 ted deletion or transgenic overexpression of ATGL exclusively in skeletal muscle.

169 Overexpression of ATGL in these cells antagonized the lipogenic effect of

170 f myocardial TAG, and that overexpression of ATGL is sufficient to ameliorate diabetes-induced cardio

171 Interestingly, overexpression of ATGL restored the lipolytic rates in cells with silenced

172 ted PKA, which led to the phosphorylation of ATGL and HSL and their recruitment to the LD surface.

173 d triglyceride breakdown and prolongation of ATGL half-life in adipose tissue.

174 However, regulation of ATGL expression and its functional implications in hepat

175 a new model of transcriptional regulation of ATGL.

176 However, the physiological relevance of ATGL-mediated triacylglycerol hydrolysis in skeletal mus

177 ting hepatic steatosis through repression of ATGL expression.

178 findings unravel a novel protective role of ATGL against hepatic inflammation which could have impor

179 g through PPARalpha, we explored the role of ATGL in hepatic inflammation in mouse models of NASH and

180 The selectivity of ATGL broadens to the sn-1 position upon stimulation of t

181 Silencing of ATGL expression in adipocytes almost completely abolishe

182 of hepatic lipid metabolism requires optimum ATGL expression for its metabolic outcome.

183 Adenoviral overexpression of HSL and/or ATGL reduced liver triglycerides by 40-60% in both ob/ob

184 In summary, hepatic overexpression of HSL or ATGL can promote fatty acid oxidation, stimulate direct

185 lls with adenoviral overexpression of HSL or ATGL showed that reduced cellular triglycerides could be

186 imulated lipolysis mediated by overexpressed ATGL or CGI-58.

187 alpha) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fs

188 We conclude that G0S2 acts as a potent ATGL inhibitor in the heart modulating cardiac substrate

189 Both proteins independently recruited ATGL to the LD surface, but with opposite effects; inter

190 he first demonstration that Peri A regulates ATGL-dependent lipolysis and identify serine 517 as the

191 n UCP1 mRNA (p = 0.03) and lipolysis-related ATGL mRNA (p = 0.04).

192 s ATGL deficiency and cardiomyocyte-specific ATGL overexpression.

193 Glucose tolerance tests demonstrated that ATGL knockdown normalized glucose tolerance in HF-diet-f

194 Here we show that ATGL exhibits a strong preference for the hydrolysis of

195 The results show that ATGL interacts with CGI-58 and perilipin 5; the latter i

196 Taken together, these data show that ATGL is a major hepatic TAG lipase that plays an integra

197 This suggests that ATGL and diacylglycerol-O-acyltransferase 2 act coordina

198 rget gene expression, and this suggests that ATGL influences PPAR-alpha activity independently of lig

199 s the expression of luciferase driven by the ATGL promotor.

200 a treatment caused a rapid abrogation of the ATGL inhibitory protein G0S2.

201 the effect of Tor1 on the expression of the ATGL ortholog in yeast.

202 rients and directly inhibits activity of the ATGL promoter in vitro and expression of ATGL in culture

203 FSP27 suppresses the activity of the ATGL promoter in vitro, and the proximal Egr1 binding si

204 s its association with and inhibition of the ATGL promoter.

205 reduction in expression of either HSL or the ATGL coactivator CGI-58.

206 hat core does not directly interact with the ATGL complex but, unexpectedly, increased the interactio

207 c acid (PA/OA) ratio in WT mice, compared to ATGL KO mice, at baseline.

208 r findings show that UBXD8 binds directly to ATGL and promotes dissociation of its endogenous coactiv

209 n than hearts with a lipolytic defect due to ATGL deficiency.

210 inflammation in both MCD-fed and LPS-treated ATGL-KO mice.

211 erol O-acyltransferase 1) and degrade LD via ATGL (adipocyte triglyceride lipase) after FA loading.

212 r perilipin 1 nor 2 interacted directly with ATGL.

213 s by direct protein-protein interaction with ATGL.

214 27, amino acids 120-220, that interacts with ATGL to inhibit its lipolytic function and promote trigl

215 Studies with ATGL-and HSL-directed small hairpin RNAs demonstrate tha