共查询到20条相似文献,搜索用时 46 毫秒
1.
Hironori Adachi Tatsuya Kondo Rei Ogawa Norio Ishii Keishi Miyata Hiroyuki Motoshima Kaku Tsuruzoe Motohiro Takeya Gou Young Koh Toshio Suda Eiichi Araki 《Biochemical and biophysical research communications》2009,379(4):806-355
Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE−/−Angptl 4−/− mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE−/−Angptl 4−/− mice compared with and ApoE−/−Angptl 4+/+ mice. There was a significant (75 ± 12%) reduction in atherosclerotic lesion size in ApoE−/−Angptl 4−/− mice compared with ApoE−/− Angptl 4+/+ mice. Peritoneal macrophages, isolated from Angptl 4−/− mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4+/+ mice. Thus, genetic knockout of Angptl 4 protects ApoE−/− mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro. 相似文献
2.
Kazutaka Miyatake Koji Washio Akiho Yokota Yoshihisa Nakano Shozaburo Kitaoka 《Bioscience, biotechnology, and biochemistry》2013,77(10):2651-2653
We investigated the hypolipidemic effects of young persimmon fruit (YP) on apolipoprotein E-deficient C57BL/6.KOR-ApoEshl mice. These mice exhibited higher plasma cholesterols, except for high-density lipoprotein (HDL), and lower plasma HDL cholesterol than C57BL/6.Cr mice that had the same genetic background as the C57BL/6.KOR-ApoEshl mice. Male C57BL/6.KOR-ApoEshl mice (n=5) were fed a diet supplemented with dry YP, Hachiya-kaki, at a concentration of 5% (w/w) for 10 weeks. YP treatment significantly lowered plasma chylomicron, very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterols, and triglyceride, and this response was accompanied by an elevation of fecal bile acid excretion. In the liver, sterol regulatory element binding protein-2 gene expression was significantly higher in mice fed YP, while the mRNA and protein levels of the LDL receptor did not change. These results indicate that acceleration of fecal bile acid excretion is a major mechanism of the hypolipidemic effect induced by YP in C57BL/6.KOR-ApoEshl mice. 相似文献
3.
4.
Qiaoling Yao Mi-Kyung Shin Jonathan C. Jun Karen L. Hernandez Neil R. Aggarwal Jason R. Mock Jason Gay Luciano F. Drager Vsevolod Y. Polotsky 《Journal of lipid research》2013,54(4):1058-1065
Chronic intermittent hypoxia (CIH) inhibits plasma lipoprotein clearance and adipose lipoprotein lipase (LPL) activity in association with upregulation of an LPL inhibitor angiopoietin-like protein 4 (Angptl4). We hypothesize that CIH inhibits triglyceride (TG) uptake via Angptl4 and that an anti-Angptl4-neutralizing antibody would abolish the effects of CIH. Male C57BL/6J mice were exposed to four weeks of CIH or intermittent air (IA) while treated with Ab (30 mg/kg ip once a week). TG clearance was assessed by [H3]triolein administration retroorbitally. CIH delayed TG clearance and suppressed TG uptake and LPL activity in all white adipose tissue depots, brown adipose tissue, and lungs, whereas heart, liver, and spleen were not affected. CD146+ CD11b− pulmonary microvascular endothelial cells were responsible for TG uptake in the lungs and its inhibition by CIH. Antibody to Angptl4 decreased plasma TG levels and increased TG clearance and uptake into adipose tissue and lungs in both control and CIH mice to a similar extent, but did not reverse the effects of CIH. The antibody reversed the effects of CIH on LPL in adipose tissue and lungs. In conclusion, CIH inactivates LPL by upregulating Angptl4, but inhibition of TG uptake occurs predominantly via an Angptl4/LPL-independent mechanism. 相似文献
5.
E-Chiang Lee Urvi Desai Gennady Gololobov Seokjoo Hong Xiao Feng Xuan-Chuan Yu Jason Gay Nat Wilganowski Cuihua Gao Ling-Ling Du Joan Chen Yi Hu Sharon Zhao Laura Kirkpatrick Matthias Schneider Brian P. Zambrowicz Greg Landes David R. Powell William K. Sonnenburg 《The Journal of biological chemistry》2009,284(20):13735-13745
Angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are
secreted proteins that regulate triglyceride (TG) metabolism in part by
inhibiting lipoprotein lipase (LPL). Recently, we showed that treatment of
wild-type mice with monoclonal antibody (mAb) 14D12, specific for ANGPTL4,
recapitulated the Angptl4 knock-out (-/-) mouse phenotype of reduced
serum TG levels. In the present study, we mapped the region of mouse ANGPTL4
recognized by mAb 14D12 to amino acids
Gln29–His53, which we designate as specific
epitope 1 (SE1). The 14D12 mAb prevented binding of ANGPTL4 with LPL,
consistent with its ability to neutralize the LPL-inhibitory activity of
ANGPTL4. Alignment of all angiopoietin family members revealed that a sequence
similar to ANGPTL4 SE1 was present only in ANGPTL3, corresponding to amino
acids Glu32–His55. We produced a mouse mAb against
this SE1-like region in ANGPTL3. This mAb, designated 5.50.3, inhibited the
binding of ANGPTL3 to LPL and neutralized ANGPTL3-mediated inhibition of LPL
activity in vitro. Treatment of wild-type as well as hyperlipidemic
mice with mAb 5.50.3 resulted in reduced serum TG levels, recapitulating the
lipid phenotype found in Angptl3-/- mice. These results
show that the SE1 region of ANGPTL3 and ANGPTL4 functions as a domain
important for binding LPL and inhibiting its activity in vitro and
in vivo. Moreover, these results demonstrate that therapeutic
antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of
some forms of hyperlipidemia.Lipoprotein lipase
(LPL)5 plays a pivotal
role in lipid metabolism by catalyzing the hydrolysis of plasma triglycerides
(TGs). LPL is likely to be regulated by mechanisms that depend on nutritional
status and on the tissue in which it is expressed
(1–3).
Two secreted proteins, angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4
(ANGPTL4), play important roles in the regulation of LPL activity
(4,
5). ANGPTL3 and ANGPTL4 consist
of a signal peptide, an N-terminal segment containing coiled-coil domains, and
a C-terminal fibrinogen-like domain. The N-terminal segment as well as
full-length ANGPTL3 and ANGPTL4 have been shown to inhibit LPL activity, and
deletion of the N-terminal segment of ANGPTL3 and ANGPTL4 resulted in total
loss of LPL-inhibiting activity
(6,
7). These observations clearly
indicate that the N-terminal region of ANGPTL4 contains the functional domain
that inhibits LPL and affects plasma lipid levels. The coiled-coil domains
have been proposed to be responsible for oligomerization
(8); however, it is not known
whether the coiled-coil domains directly mediate the inhibition of LPL
activity.To define the physiological role of ANGPTL4 more clearly, we characterized
the pharmacological consequences of ANGPTL4 inhibition in mice treated with
the ANGPTL4-neutralizing monoclonal antibody (mAb) 14D12
(9). Injection of mAb 14D12
significantly lowered fasting TG levels in C57BL/6J mice relative to levels in
C57BL/6J mice treated with an isotype-matched anti-KLH control (KLH) mAb
(9). These reduced TG values
were similar to decreases in fasting plasma TG levels measured in
Angptl4 knock-out (-/-) mice. This study demonstrated that mAb 14D12
is a potent ANGPTL4-neutralizing antibody that is able to inhibit systemic
ANGPTL4 activity and thereby recapitulate the reduced lipid phenotype found in
Angptl4-/- mice. The readily apparent pharmacological
effect of mAb 14D12 prompted new questions about the epitope recognized by mAb
14D12 and how this antibody-antigen binding event affected ANGPTL4 function as
an LPL inhibitor.Although ANGPTL4 is able to interact directly with LPL
(10), it is not clear which
amino acids within ANGPTL4 mediate this interaction. Here we show that amino
acids Gln29–His53 of mANGPTL4 contain the epitope
for mAb 14D12. This region, hereby designated specific epitope 1 (SE1), also
defines a domain that mediates the interaction between ANGPTL4 and LPL and the
subsequent inactivation of LPL. With this information we present evidence that
ANGPTL3 also contains an SE1 region, and with antibodies specifically reactive
with ANGPTL3 SE1 we examine whether the ANGPTL3 SE1 region is involved in LPL
binding and inhibition. We also determined whether treatment of C57BL/6 mice
with an anti-ANGPTL3 SE1 mAb can recapitulate the phenotype of lower serum TG
and cholesterol levels found in Angptl3-/- mice. Finally
we tested the therapeutic potential of an anti-ANGPTL3 SE1 mAb for treatment
of hyperlipidemia in apolipoprotein E-/-
(ApoE-/-) or low density lipoprotein
receptor-/- (LDLr-/-) mice. 相似文献
6.
A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice 总被引:6,自引:0,他引:6
Ando Y Shimizugawa T Takeshita S Ono M Shimamura M Koishi R Furukawa H 《Journal of lipid research》2003,44(6):1216-1223
KK/Snk mice (previously KK/San) possessing a recessive mutation (hypl) of the angiopoietin-like 3 (Angptl3) gene homozygously exhibit a marked reduction of VLDL due to the decreased Angptl3 expression. Recently, we proposed that Angptl3 is a new class of lipid metabolism modulator regulating VLDL triglyceride (TG) levels through the inhibition of lipoprotein lipase (LPL) activity. In this study, to elucidate the role of Angptl3 in atherogenesis, we investigated the effects of hypl mutation against hyperlipidemia and atherosclerosis in apolipoprotein E knockout (apoEKO) mice. ApoEKO mice with hypl mutation (apoEKO-hypl) exhibited a significant reduction of VLDL TG, VLDL cholesterol, and plasma apoB levels compared with apoEKO mice. Hepatic VLDL TG secretion was comparable between both apoE-deficient mice. Turnover studies revealed that the clearance of both [3H]TG-labeled and 125I-labeled VLDL was significantly enhanced in apoEKO-hypl mice. Postprandial plasma TG levels also decreased in apoEKO-hypl mice. Both LPL and hepatic lipase activities in the postheparin plasma increased significantly in apoEKO-hypl mice, explaining the enhanced lipid metabolism. Furthermore, apoEKO-hypl mice developed 3-fold smaller atherogenic lesions in the aortic sinus compared with apoEKO mice. Taken together, the reduction of Angptl3 expression is protective against hyperlipidemia and atherosclerosis, even in the absence of apoE, owing to the enhanced catabolism and clearance of TG-rich lipoproteins. 相似文献
7.
Eleni A. Karavia Dionysios J. Papachristou Ioanna Kotsikogianni Irene-Eva Triantafyllidou Kyriakos E. Kypreos 《The Journal of nutritional biochemistry》2013,24(3):567-577
Lecithin/cholesterol acyltransferase (LCAT) is responsible for the esterification of the free cholesterol of plasma lipoproteins. Here, we investigated the involvement of LCAT in mechanisms associated with diet-induced hepatic triglyceride accumulation in mice. LCAT-deficient (LCAT?/?) and control C57BL/6 mice were placed on a Western-type diet (17.3% protein, 48.5% carbohydrate, 21.2% fat, 0.2% cholesterol, 4.5 kcal/g) for 24 weeks, then histopathological and biochemical analyses were performed. We report that, in our experimental setup, male LCAT?/? mice are characterized by increased diet-induced hepatic triglyceride deposition and impaired hepatic histology and architecture. Mechanistic analyses indicated that LCAT deficiency was associated with enhanced intestinal absorption of dietary triglycerides (3.6±0.5 mg/dl per minute for LCAT?/? vs. 2.0±0.7 mg/dl per minute for C57BL/6 mice; P<.05), accelerated clearance of postprandial triglycerides and a reduced rate of hepatic very low density lipoprotein triglyceride secretion (9.8±1.1 mg/dl per minute for LCAT?/? vs. 12.5±1.3 mg/dl per minute for C57BL/6 mice, P<.05). No statistical difference in the average daily food consumption between mouse strains was observed. Adenovirus-mediated gene transfer of LCAT in LCAT?/? mice that were fed a Western-type diet for 12 weeks resulted in a significant reduction in hepatic triglyceride content (121.2±5.9 mg/g for control infected mice vs. 95.1±5.8 mg/g for mice infected with Ad-LCAT, P<.05) and a great improvement of hepatic histology and architecture. Our data extend the current knowledge on the functions of LCAT, indicating that LCAT activity is an important modulator of processes associated with diet-induced hepatic lipid deposition. 相似文献
8.
《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2022,1867(10):159196
Elevated plasma levels of low-density lipoprotein-C (LDL-C) increase the risk of atherosclerotic cardiovascular disease. Circulating LDL is derived from very low-density lipoprotein (VLDL) metabolism and cleared by LDL receptor (LDLR). We have previously demonstrated that cargo receptor Surfeit 4 (Surf4) mediates VLDL secretion. Inhibition of hepatic Surf4 impairs VLDL secretion, significantly reduces plasma LDL-C levels, and markedly mitigates the development of atherosclerosis in LDLR knockout (Ldlr?/?) mice. Here, we investigated the role of Surf4 in lipoprotein metabolism and the development of atherosclerosis in another commonly used mouse model of atherosclerosis, apolipoprotein E knockout (apoE?/?) mice. Adeno-associated viral shRNA was used to silence Surf4 expression mainly in the liver of apoE?/? mice. In apoE?/? mice fed a regular chow diet, knockdown of Surf4 expression significantly reduced triglyceride secretion and plasma levels of non-HDL cholesterol and triglycerides without causing hepatic lipid accumulation or liver damage. When Surf4 was knocked down in apoE?/? mice fed the Western-type diet, we observed a significant reduction in plasma levels of non-HDL cholesterol, but not triglycerides. Knockdown of Surf4 did not increase hepatic cholesterol and triglyceride levels or cause liver damage, but significantly diminished atherosclerosis lesions. Therefore, our findings indicate the potential of hepatic Surf4 inhibition as a novel therapeutic strategy to reduce the risk of atherosclerotic cardiovascular disease. 相似文献
9.
Leptin and insulin down-regulate angiopoietin-like protein 3, a plasma triglyceride-increasing factor 总被引:4,自引:0,他引:4
Shimamura M Matsuda M Ando Y Koishi R Yasumo H Furukawa H Shimomura I 《Biochemical and biophysical research communications》2004,322(3):1080-1085
We reported previously that angiopoietin-like protein3 (ANGPTL3), a liver-specific secretory factor, increased plasma triglyceride (TG) via inhibition of lipoprotein lipase and free fatty acid (FFA) by activating adipose-lipolysis. The current study examined the regulation of Angptl3 by leptin and insulin, both of which are key players in the metabolic syndrome. Angptl3 expression and plasma ANGPTL3 levels were increased in leptin-resistant C57BL/6J(db/db) and -deficient C57BL/6J(ob/ob) mice, relative to the control. Leptin supplements decreased Angptl3 gene expression and plasma ANGPTL3 in C57BL/6J(ob/ob) mice. The changes of Angptl3 were associated with alterations of plasma TG and FFA levels. Leptin treatment directly suppressed Angptl3 gene expression in hepatocytes. Angptl3 gene expression and plasma protein levels were also increased in insulin-deficient streptozotocin-treated mice. Insulin treatment of hepatocytes decreased Angptl3 gene expression and protein secretion. Our results suggest that elevated ANGPTL3 by leptin- or insulin-resistance is attributed to increased plasma TG and FFA concentrations in obesity. 相似文献
10.
Adachi H Kondo T Koh GY Nagy A Oike Y Araki E 《Biochemical and biophysical research communications》2011,409(2):177-180
Angiopoietin-like protein family 4 (Angptl4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). In familial hypercholesterolemia (FH), individuals lacking low-density lipoprotein receptor (LDLR) present not only hypercholesterolemia, but also increased plasma triglyceride (TG)-rich lipoprotein remnants, and develop atherosclerosis. In addition, the most common type of dyslipidemia in individuals with diabetes is increased TG levels.We first generated LDLR−/−Angptl4−/− mice to study the effect of Angptl4 deficiency on the lipid metabolism. Fasting total cholesterol, VLDL-C, LDL-C, HDL-C and TG levels were decreased in LDLR−/−Angptl4−/− mice compared with LDLR−/−Angptl4+/+ mice. In particular, post olive oil-loaded TG excursion were largely attenuated in LDLR−/−Angptl4−/− mice compared with LDLR−/−Angptl4+/+ mice. We next introduced diabetes by streptozotocin (STZ) treatment in Angptl4−/− mice and examined the impacts of Angptl4 deficiency. Compared with diabetic Angptl4+/+ mice, diabetic Angptl4−/− mice showed the improvement of fasting and postprandial hypertriglyceridemia as well. Thus, targeted silencing of Angptl4 offers a potential therapeutic strategy for the treatment of dyslipidemia in individuals with FH and insulin deficient diabetes. 相似文献
11.
Ming-hon Yau Yu Wang Karen S. L. Lam Jialiang Zhang Donghai Wu Aimin Xu 《The Journal of biological chemistry》2009,284(18):11942-11952
Lipoprotein lipase (LPL) is a principal enzyme responsible for the
clearance of chylomicrons and very low density lipoproteins from the
bloodstream. Two members of the Angptl (angiopoietin-like protein) family,
namely Angptl3 and Angptl4, have been shown to inhibit LPL activity in
vitro and in vivo. Here, we further investigated the structural
basis underlying the LPL inhibition by Angptl3 and Angptl4. By multiple
sequence alignment analysis, we have identified a highly conserved 12-amino
acid consensus motif that is present within the coiled-coil domain (CCD) of
both Angptl3 and Angptl4, but not other members of the Angptl family.
Substitution of the three polar amino acid residues (His46,
Gln50, and Gln53) within this motif with alanine
abolishes the inhibitory effect of Angptl4 on LPL in vitro and also
abrogates the ability of Angptl4 to elevate plasma triglyceride levels in
mice. The CCD of Angptl4 interacts with LPL and converts the catalytically
active dimers of LPL to its inactive monomers, whereas the mutant protein with
the three polar amino acids being replaced by alanine loses such a property.
Furthermore, a synthetic peptide consisting of the 12-amino acid consensus
motif is sufficient to inhibit LPL activity, although the potency is
much lower than the recombinant CCD of Angptl4. In summary, our data suggest
that the 12-amino acid consensus motif within the CCD of Angptl4, especially
the three polar residues within this motif, is responsible for its interaction
with and inhibition of LPL by blocking the enzyme dimerization.Lipoprotein lipase
(LPL)3 is an
endothelium-bound enzyme that catalyzes the hydrolysis of plasma triglyceride
(TG) associated with chylomicrons and very low density lipoproteins
(1,
2). This enzyme plays a major
role in maintaining lipid homeostasis by promoting the clearance of TG-rich
lipoproteins from the bloodstream. Abnormality in LPL functions has been
associated with a number of pathological conditions, including
atherosclerosis, dyslipidemia associated with diabetes, and Alzheimer disease
(1).LPL is expressed in a wide variety of cell types, particularly in
adipocytes and myocytes (2). As
a rate-limiting enzyme for clearance of TG-rich lipoproteins, the activity of
LPL is tightly modulated by multiple mechanisms in a tissue-specific manner in
response to nutritional changes
(3,
4). The enzymatic activity of
LPL in adipose tissue is enhanced after feeding to facilitate the storage of
TG, whereas it is down-regulated during fasting to increase the utilization of
TG by other tissues (5). The
active form of LPL is a noncovalent homodimer with the subunits associated in
a head-to-tail manner, and the dissociation of its dimeric form leads to the
formation of a stable inactive monomeric conformation and irreversible enzyme
inactivation (6). At the
post-translational level, the LPL activity is regulated by numerous
apolipoprotein co-factors. For instance, apoCII, a small apolipoprotein
consisting of 79 amino acid residues in human, activates LPL by directly
binding to the enzyme (7,
8). By contrast, several other
apolipoproteins such as apoCI, apo-CIII, and apoE have been shown to inhibit
the LPL activity in vitro
(3).Angiopoietin-like proteins (Angptl) are a family of secreted proteins
consisting of seven members, Angptl1 to Angptl7
(9,
10). All the members of the
Angptl family share a similar domain organization to those of angiopoietins,
with an NH2-terminal coiled-coil domain (CCD) and a COOH-terminal
fibrinogen-like domain. Among the seven family members, only Angptl3 and
Angptl4 have been shown to be involved in regulating triglyceride metabolism
(10,
11). The biological functions
of Angptl3 in lipid metabolism were first discovered by Koishi et al.
(12) in their positional
cloning of the recessive mutation gene responsible for the hypolipidemia
phenotype in a strain of obese mouse KK/snk. Subsequent studies have
demonstrated that Angptl3 increases plasma TG levels by inhibiting the LPL
enzymatic activity
(13–15).
Angptl4, also known as fasting-induced adipocyte factor, hepatic
fibrinogen/angiopoietin-related protein, or peroxisome proliferator-activated
receptor-γ angiopoietin-related, is a secreted glycoprotein abundantly
expressed in adipocyte, liver, and placenta
(16–18).
In addition to its role in regulating angiogenesis, a growing body of evidence
demonstrated that Angptl4 is an important player of lipid metabolism
(10,
11). Elevation of circulating
Angptl4 by transgenic or adenoviral overexpression, or by direct
supplementation of recombinant protein, leads to a marked elevation in the
levels of plasma TG and low density lipoprotein cholesterol in mice
(19–22).
By contrast, Angptl4 knock-out mice exhibit much lower plasma TG and
cholesterol levels compared with the wild type littermates
(19,
20). Notably, treatment of
several mouse models (such as C57BL/6J, ApoE–/–,
LDLR–/–, and db/db obese/diabetic mice) with a
neutralizing antibody against Angptl4 recapitulate the lipid phenotype found
in Angptl4 knock-out mice
(19). The role of Angptl4 as a
physiological inhibitor of LPL is also supported by the finding that its
expression levels in adipose tissue change rapidly during the fed-to-fasting
transitions and correlate inversely with LPL activity
(23). In humans, a genetic
variant of the ANGPTL4 gene (E40K) has been found to be associated
with significantly lower plasma TG levels and higher high density lipoprotein
cholesterol concentrations in several ethnic groups
(24–26).Angptl3 and Angptl4 share many common biochemical and functional properties
(10). In both humans and
rodents, Angptl3 and Angptl4 are proteolytically cleaved at the linker region
and circulate in plasma as two truncated fragments, including
NH2-terminal CCD and COOH-terminal fibrinogen-like domain
(14,
27–29).
The effects of both Angptl3 and Angptl4 on elevating plasma TG levels are
mediated exclusively by their NH2-terminal CCDs
(15,
22,
23,
27,
30). The CCDs of Angptl3 and
Angptl4 have been shown to inhibit the LPL activity in vitro as well
as in mice
(23,30,31).
Angptl4 inhibits LPL by promoting the conversion of the catalytically active
LPL dimers into catalytically inactive LPL monomers, thereby leading to the
inactivation of LPL (23,
31). However, the detailed
structural and molecular basis underlying the LPL inhibition by Angptl3 and
Angptl4 remain poorly characterized at this stage.In this study, we analyzed all known amino acid sequences of Angptl3 and
Angptl4 from various species and found a short motif,
LAXGLLXLGXGL (where X represents polar
amino acid residues), which corresponds to amino acid residues 46–57 and
44–55 of human Angptl3 and Angptl4, respectively, is highly conserved
despite the low degree of their overall homology (∼30%). Using both in
vitro and in vivo approaches, we demonstrated that this 12-amino
acid sequence motif, in particular the three polar amino acid residue within
this motif, is essential for mediating the interactions between LPL and
Angpt4, which in turn disrupts the dimerization of the enzyme. 相似文献
12.
13.
Angiopoietin-like protein 3 mediates hypertriglyceridemia induced by the liver X receptor 总被引:18,自引:0,他引:18
Inaba T Matsuda M Shimamura M Takei N Terasaka N Ando Y Yasumo H Koishi R Makishima M Shimomura I 《The Journal of biological chemistry》2003,278(24):21344-21351
The KK/San obese and diabetic mouse, a mutant strain from KK obese mice, exhibits significantly low plasma triglyceride levels. In KK/San mice, genetic analysis identified a mutation in the gene encoding angiopoietinlike protein 3 (Angptl3), a liver-specific secretory protein, which had suppressive effect on lipoprotein lipase activity. In the current study, LXR ligands augmented Angptl3 mRNA expression and protein production in hepatoma cells. LXR ligands and LXR.retinoid X receptor (RXR) complex increased the promoter activity of Angptl3 gene. Serial deletion and point mutation of Angptl3 promoter identified an LXR response element (LXRE). Gel mobility shift assay showed the direct binding of LXR.RXR complex to the LXRE of the Angptl3 promoter. Furthermore, treatment of mice with synthetic LXR ligand caused triglyceride accumulation in the liver and plasma, which was accompanied by induction of hepatic mRNAs of several LXR target genes, including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and Angptl3. In Angptl3-deficient C57BL/6J mice, LXR ligand did not cause hypertriglyceridemia but accumulation of triglyceride in the liver. Our results demonstrate that Angptl3 is a direct target of LXR and that induction of hepatic Angptl3 accounts for hypertriglyceridemia associated with the treatment of LXR ligand. 相似文献
14.
William K. Sonnenburg Daiguan Yu E-Chiang Lee Wei Xiong Gennady Gololobov Billie Key Jason Gay Nat Wilganowski Yi Hu Sharon Zhao Matthias Schneider Zhi-Ming Ding Brian P. Zambrowicz Greg Landes David R. Powell Urvi Desai 《Journal of lipid research》2009,50(12):2421-2429
Glycosylphosphatidylinositol-anchored HDL-binding protein (GPIHBP1) binds both LPL and chylomicrons, suggesting that GPIHBP1 is a platform for LPL-dependent processing of triglyceride (TG)-rich lipoproteins. Here, we investigated whether GPIHBP1 affects LPL activity in the absence and presence of LPL inhibitors angiopoietin-like (ANGPTL)3 and ANGPTL4. Like heparin, GPIHBP1 stabilized but did not activate LPL. ANGPTL4 potently inhibited nonstabilized LPL as well as heparin-stabilized LPL but not GPIHBP1-stabilized LPL. Like ANGPTL4, ANGPTL3 inhibited nonstabilized LPL but not GPIHBP1-stabilized LPL. ANGPTL3 also inhibited heparin-stabilized LPL but with less potency than nonstabilized LPL. Consistent with these in vitro findings, fasting serum TGs of Angptl4−/−/Gpihbp1−/− mice were lower than those of Gpihbp1−/− mice and approached those of wild-type littermates. In contrast, serum TGs of Angptl3−/−/Gpihbp1−/− mice were only slightly lower than those of Gpihbp1−/− mice. Treating Gpihbp1−/− mice with ANGPTL4- or ANGPTL3-neutralizing antibodies recapitulated the double knockout phenotypes. These data suggest that GPIHBP1 functions as an LPL stabilizer. Moreover, therapeutic agents that prevent LPL inhibition by ANGPTL4 or, to a lesser extent, ANGPTL3, may benefit individuals with hyperlipidemia caused by gene mutations associated with decreased LPL stability. 相似文献
15.
The aim of the study was to investigate long-term effects of radiation on the (ultra)structure and function of the liver in mice. The experiments were conducted on wild-type C57BL/6J and apolipoprotein E knock-out (ApoE?/?) male mice which received a single dose (2 or 8 Gy) of X-rays to the heart with simultaneous exposure of liver to low doses (no more than 30 and 120 mGy, respectively). Livers were collected for analysis 60 weeks after irradiation and used for morphological, ultrastructural, and biochemical studies. The results show increased damage to mitochondrial ultrastructure and lipid deposition in hepatocytes of irradiated animals as compared to non-irradiated controls. Stronger radiation-related effects were noted in ApoE?/? mice than wild-type animals. In contrast, radiation-related changes in the activity of lysosomal hydrolases, including acid phosphatase, β-glucuronidase, N-acetyl-β-d-hexosaminidase, β-galactosidase, and α-glucosidase, were observed in wild type but not in ApoE-deficient mice, which together with ultrastructural picture suggests a higher activity of autophagy in ApoE-proficient animals. Irradiation caused a reduction of plasma markers of liver damage in wild-type mice, while an increased level of hepatic lipase was observed in plasma of ApoE-deficient mice, which collectively indicates a higher resistance of hepatocytes from ApoE-proficient animals to radiation-mediated damage. In conclusion, liver dysfunctions were observed as late effects of irradiation with an apparent association with malfunction of lipid metabolism. 相似文献
16.
《Journal of lipid research》2018,59(1):144-154
High plasma cholesterol levels are found in several metabolic disorders and their reductions are advocated to reduce the risk of atherosclerosis. A way to lower plasma lipids is to curtail lipoprotein production; however, this is associated with steatosis. We previously showed that microRNA (miR)-30c lowers diet-induced hypercholesterolemia and atherosclerosis in C57BL/6J and Apoe−/− mice. Here, we tested the effect of miR-30c on plasma lipids, transaminases, and hepatic lipids in different mouse models. Hepatic delivery of miR-30c to chow-fed leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) hypercholesterolemic and hyperglycemic mice reduced cholesterol in total plasma and VLDL/LDL by ∼28% and ∼25%, respectively, without affecting triglyceride and glucose levels. And these mice had lower plasma transaminases and creatine kinase activities than controls. Moreover, miR-30c significantly lowered plasma cholesterol and atherosclerosis in Western diet-fed Ldlr−/− mice with no effect on plasma triglyceride, glucose, and transaminases. In these studies, hepatic lipids were similar in control and miR-30c-injected mice. Mechanistic studies showed that miR-30c reduced hepatic microsomal triglyceride transfer protein activity and lipid synthesis. Thus miR-30c reduced plasma cholesterol in several diet-induced and diabetic hypercholesterolemic mice. We speculate that miR-30c may be beneficial in lowering plasma cholesterol in different metabolic disorders independent of the origin of hypercholesterolemia. 相似文献
17.
Hong Zhu Zeng Wang Zhen Dong Cong Wang Quan Cao Fan Fan Jingjing Zhao Xiangwei Liu Meng Yuan Xiaolei Sun Xiuhua Peng Yunzeng Zou Jingmin Zhou Junbo Ge Xiaohui Zhou Yingmei Zhang 《生物化学与生物物理学报:疾病的分子基础》2019,1865(7):1782-1792
Previous evidence has indicated a beneficial role for aldehyde dehydrogenase 2 (ALDH2) in suppressing atherosclerotic plaque progression and instability. However, the underlying mechanism remains somewhat elusive. This study was designed to examine the effect of ALDH2 deficiency on high-cholesterol diet-induced atherosclerotic plaque progression and plaque vulnerability in atherosclerosis-prone ApoE knockout (ApoE?/?) mice with a focus on foam cell formation in macrophages and senescence of vascular smooth muscle cells (VSMCs). Serum lipid profile, plaque progression, and plaque vulnerability were examined in ApoE?/? and ALDH2/ApoE double knockout (ALDH2?/?ApoE?/?) mice after high-cholesterol diet intake for 8 weeks. ALDH2 deficiency increased the serum levels of triglycerides while it decreased levels of total cholesterol and high-density lipoprotein cholesterol. Unexpectedly, ALDH2 deficiency reduced the plaque area by 58.9% and 37.5% in aorta and aortic sinus, respectively. Plaque instability was aggravated by ALDH2 deficiency along with the increased necrotic core size, decreased collagen content, thinner fibrous cap area, decreased VSMC content, and increased macrophage content. In atherosclerotic lesions, ALDH2 protein was located in both macrophages and VSMCs. Further results revealed downregulated ALDH2 expression in aorta of aged ApoE?/? mice compared with young mice. However, in vitro study suggested that ALDH2 expression was upregulated in bone marrow-derived macrophages (BMDMs) with an opposite effect in VSMCs following 80 μg/ml oxidized low-density lipoprotein (oxLDL) treatment. Interestingly, ALDH2 deficiency displayed little effect in oxLDL-induced foam cell formation from BMDMs, while ALDH2 knockdown by siRNA and ALDH2 overexpression by lentivirus infection promoted and retarded oxLDL-induced VSMC senescence, respectively. Mechanistically, ALDH2 mitigated oxLDL-induced overproduction of mitochondrial reactive oxygen species (mROS) and activation of downstream p53/p21/p16 pathway. Clearance of mROS by mitoTEMPO significantly reversed the promotive effect of ALDH2 knockdown on VSMC senescence. Taken together, our data revealed that ALDH2 deficiency suppressed atherosclerotic plaque area while facilitating plaque instability possibly through accelerating mROS-mediated VSMC senescence.This article is part of a Special Issue entitled: Genetic and epigenetic regulation of aging and longevity edited by Jun Ren & Megan Yingmei Zhang. 相似文献
18.
Peng-Li Zhou Min Li Xin-Wei Han Yong-Hua Bi Wen-Guang Zhang Zheng-Yang Wu Gang Wu 《Journal of cellular biochemistry》2019,120(11):19107-19123
Excessive plasma triglyceride (TG) and cholesterol levels promote the progression of several prevalent cardiovascular risk factors, including atherosclerosis, which is a leading death cause. Perilipin 5 (Plin5), an important perilipin protein, is abundant in tissues with very active lipid catabolism and is involved in the regulation of oxidative stress. Although inflammation and oxidative stress play a critical role in atherosclerosis development, the underlying mechanisms are complex and not completely understood. In the present study, we demonstrated the role of Plin5 in high-fat-diet-induced atherosclerosis in apolipoprotein E null (ApoE−/−) mice. Our results suggested that Plin5 expressions increased in the artery tissues of ApoE−/− mice. ApoE/Plin5 double knockout (ApoE−/−Plin5−/−) exacerbated severer atherogenesis, accompanied with significantly disturbed plasma metabolic profiles, such as elevated TG, total cholesterol, and low-density lipoprotein cholesterol levels and reduced high-density lipoprotein cholesterol contents. ApoE−/−Plin5−/− exhibited a higher number of inflammatory monocytes and neutrophils, as well as overexpression of cytokines and chemokines linked with an inflammatory response. Consistently, the IκBα/nuclear factor kappa B pathway was strongly activated in ApoE−/−Plin5−/−. Notably, apoptosis was dramatically induced by ApoE−/−Plin5−/−, as evidenced by increased cleavage of Caspase-3 and Poly (ADP-ribose) polymerase-2. In addition, ApoE−/−Plin5−/− contributed to oxidative stress generation in the aortic tissues, which was linked with the activation of phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinases pathways. In vitro, oxidized low-density lipoprotein (ox-LDL) increased Plin5 expression in RAW264.7 cells. Its knockdown enhanced inflammation, apoptosis, oxidative stress, and lipid accumulation, while promotion of Plin5 markedly reduced all the effects induced by ox-LDL in cells. These studies strongly supported that Plin5 could be a new regulator against atherosclerosis, providing new insights on therapeutic solutions. 相似文献
19.
《Microbes and infection / Institut Pasteur》2022,24(3):104908
We examined the roles of indoleamine-2, 3-dioxygenase 1 (IDO1) in controlling cerebral Toxoplasma gondii infection in both genetically resistant and susceptible strains of mice. In susceptible C57BL/6 mice, IDO expression was immunohistochemically detected only in a minority (22.5%) of tachyzoite-infected cells in their brains during the later stage of infection. When C57BL-6-background IDO1-deficient (IDO1?/?) mice were infected, their cerebral tachyzoite burden was equivalent to those of wild-type (WT) animals. In contrast, in resistant BALB/c mice, IDO expression was detected in a majority (84.0%) of tachyzoite-infected cerebral cells. However, tachyzoite burden in BALB/c-background IDO1?/? mice remained as low as that of WT mice, which was 78 times less than those of C57BL/6 mice. Of interest, IDO1?/? mice of only resistant BALB/c-background had markedly greater cerebral expressions of two other IFN-γ-mediated effector molecules, guanylate binding protein 1 (Gbp1) and nitric oxide synthase 2 (NOS2), than their WT mice. Therefore, it would be possible that IDO1 deficiency was effectively compensated by the upregulated expression of Gbp1 and NOS2 to control cerebral tachyzoite growth in genetically resistant BALB/c mice, whereas IDO1 did not significantly contribute to controlling cerebral tachyzoite growth in genetically susceptible C57BL/6 mice because of its suppressed expression in infected cells. 相似文献
20.
Carin Gustavsson Carl-David Agardh Anna V. Zetterqvist Jan Nilsson Elisabet Agardh Maria F. Gomez 《PloS one》2010,5(9)