Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart

Yu, Xinxin; Burgess, Shawn C.; Ge, Hongfei; Wong, Kenny K.; Nassem, R. Haris; Garry, Daniel J.; Sherry, A. Dean; Malloy, Craig R.; Berger, Joel P.; Cai, Li

doi:10.1073/pnas.0409564102

Cited by 96 publications

(69 citation statements)

References 48 publications

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“…The TG increase was due to a rise in circulating very low-density lipoprotein (VLDL) (6,8,10). This phenomenon likely resulted from decreased VLDL clearance secondary to the lower LPL activity measured in vivo (8,9), because hepatic VLDL production was unaffected (6,10). Consistent with these findings, Angptl4 knockout (Ϫ/Ϫ) mice exhibited 65-90% lower fasting TG levels and slightly lower total cholesterol levels, in addition to lower circulating VLDL and an increase in LPL activity (4,8).…”

supporting

confidence: 71%

“…Studies of Angptl4 excess or deficiency in mice strongly suggest a role for Angptl4 in the metabolism of lipids, primarily triglycerides (TGs) (5)(6)(7)(8)(9)(10). Injecting human Angptl4 (hAngptl4) into KK/San mice raised plasma TG and nonesterified fatty acids (NEFA), but not total cholesterol; the ability of Angptl4 to inhibit lipoprotein lipase (LPL) in vitro suggested this was the mechanism by which Angptl4 raised TG levels in vivo (5).…”

mentioning

confidence: 99%

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Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Desai

Lee²,

Chung³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

140

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We used gene knockout mice to explore the role of Angiopoietinlike-4 (Angptl4) in lipid metabolism as well as to generate antiAngptl4 mAbs with pharmacological activity. Angptl4 ؊/؊ mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 ؊/؊ suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE ؊/؊, LDLr ؊/؊, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 ؊/؊ mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease. monoclonal antibody ͉ mouse ͉ triglycerides ͉ cholesterol

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supporting

confidence: 71%

mentioning

confidence: 99%

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Desai

Lee²,

Chung³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

140

View full text Add to dashboard Cite

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“…A bilevel WALTZ-16 sequence was used for broad-band proton decoupling. 13 C-NMR multiplets of tissue extract glutamate were measured and used to determine the relative oxidation of [U- 13 C]FFA, [1,[6][7][8][9][10][11][12][13] C2]glucose, and unlabeled endogenous substrates (e.g., triglycerides) (24,38).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Zhao¹,

Jeoung²,

Burgess³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Kliewer SA. Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 294: H936-H943, 2008. First published December 14, 2007 doi:10.1152/ajpheart.00870.2007.-The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway. fatty acid; hypertrophy; transgenic mice THERE IS A GROWING AWARENESS that systemic perturbations in energy metabolism such as those that occur in diabetes mellitus and other forms of metabolic disease contribute to cardiovascular disease (9). The healthy heart is a metabolic omnivore capable of switching between fatty acids and carbohydrates to match energy demands with dietary and physiological conditions (30, 31). Under conditions of pressure overload and cardiac hypertrophy, increased carbohydrate oxidation is part of the adaptive response to increased workload (21). However, in diabetes the metabolic flexibility of the heart is diminished, and it becomes more reliant on fatty acids for energy (10,21,30,31). This may contribute to functional derangements by causing oxidative stress and the accumulation of harmful lipid intermediates (10,21,30,31).In heart and other tissues, competition between fatty acids and carbohydrates occurs at the level of pyruvate dehydrogenase (PDH), which catalyzes the conversion of pyruvate to acetyl-CoA, thereby linking glycolysis to the Krebs cycle and ATP production. PDH is active when glucose oxidation prevails for the generation of energy and repressed when glucose is in short supply, such as during fasting (14). Regulation of PDH is accomplished by its interconversion between an active, nonphosphorylated form and an inactive, phosphorylated form. Phosphorylation and inactivation of PDH is mediated by a family of four PDH kinases (PDK1-4) (14, 29). Expression of one of these isozymes, PDK4, is rapidly and markedly induced in heart and other tissues in response to various metabolic stimuli, including fasting and a high-fat diet (28,33,34,36). Transcription ...

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“…Although the exact role of ANGPTL4 is not clear, it appears to inhibit lipoprotein lipase 4 , an enzyme that hydrolyzes the triglycerides in circulating lipoproteins to release fatty acids for uptake by adjacent tissues 7 . Thus, ANGPTL4 may act in a paracrine manner to regulate the partitioning of fatty acids between sites of storage (adipose tissue) and sites of oxidation (heart, skeletal muscle and liver) 8 .…”

mentioning

confidence: 99%

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

et al. 2007

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Resequencing genes provides the opportunity to assess the full spectrum of variants that influence complex traits. Here we report the first application of resequencing to a large population (n = 3,551) to examine the role of the adipokine ANGPTL4 in lipid metabolism. Nonsynonymous variants in ANGPTL4 were more prevalent in individuals with triglyceride levels in the lowest quartile than in individuals with levels in the highest quartile (P = 0.016). One variant (E40K), present in ~3% of European Americans, was associated with significantly lower plasma levels of triglyceride and higher levels of high-density lipoprotein cholesterol in European Americans from the Atherosclerosis Risk in Communities Study and in Danes from the Copenhagen City Heart Study. The ratio of nonsynonymous to synonymous variants was higher in European Americans than in African Americans (4:1 versus 1.3:1), suggesting population-specific relaxation of purifying selection. Thus, resequencing of ANGPTL4 in a multiethnic population allowed analysis of the phenotypic effects of both rare and common variants while taking advantage of genetic variation arising from ethnic differences in population history.Adipocytes secrete a variety of proteins that regulate glucose and lipid metabolism 1 . The metabolic effects of these proteins have been largely deduced from studies in mice; less is Correspondence should be addressed to H.H. (helen.hobbs@utsouthwestern.edu) or J.C.C. (jonathan.cohen@utsouthwestern.edu). 7 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Genetics website.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. , most of which were rare: more than half (n = 49) were found only in one subject, and 86% (n = 80) had a minor allele frequency below 3% (Supplementary Fig. 1 and Supplementary Table 2 online). NIH Public AccessTo examine the phenotypic effects of sequence variation in ANGPTL4, we stratified the population by race, sex and trait level and then compared the number of nonsynonymous variants in the top and bottom quartiles of the distribution. We excluded variants found in both quartiles. The first trait we examined was fasting levels of plasma triglyceride. Individuals with factors known to affect triglyceride levels (lipid-lowering drugs, diabetes mellitus and heavy alcohol use) were excluded from the analyses. After these exclusions, the number of individuals with nonsynonymous sequence variants in the bottom quartile (n = 13) was significantly greater than the number in the highest quartile (n = 2; P = 0.016) (Fig. 1); we found all sequence variations in separate individuals except R336C, which was present in three European Americans in the lowest quartile of triglycerides. Although European Americans comprised less than one-third of the sample (1,045 out of 3,551), 10 of the 13 individuals with a nonsynonymou...

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Inhibition of cardiac lipoprotein utilization by transgenic overexpression of Angptl4 in the heart

Cited by 96 publications

References 48 publications

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL

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