Adipose tissue-derived autotaxin causes cardiomyopathy in obese mice

Xu, Yousheng; Wang, Yongshun; Liu, Jingjin; Cao, Wei; Li, Lili; Du, Hongwei; Zhan, Enbo; Zhang, Ruoxi; Liu, Huimin; Xu, Maoen; Chen, Tao; Qu, Yilin; Yu, Bo

doi:10.1530/jme-18-0242

Cited by 10 publications

(9 citation statements)

References 37 publications

(43 reference statements)

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“…In agreement with a prohypertrophic effect of the ATX-LPA axis on cardiomyocytes, high fat-fed (60% kcal fat) obese mice with lentiviral ATX silencing in epididymal adipose tissue showed reduced cardiac hypertrophy, which was accompanied by diminished cardiac fibrosis and steatosis [58] (Table 1). ATX silencing in WAT resulted in a drastic decline in ATX levels in adipose tissue, serum, and cardiac tissue, as well as reduced circulating LPA levels [58]. These changes were not accompanied by alterations in body weight [58].…”

Section: Studies Using Pharmacological Lpa Receptor and Atx Modulators And In Situ Atx Silencingsupporting

confidence: 64%

“…Interestingly, in humans, circulating ATX levels correlated inversely with ejection fraction and positively with the hypertrophy marker, NT-proBNP, indicating that the ATX-LPA axis may also contribute to obesity-induced cardiomyopathy in humans [35]. In agreement with a prohypertrophic effect of the ATX-LPA axis on cardiomyocytes, high fat-fed (60% kcal fat) obese mice with lentiviral ATX silencing in epididymal adipose tissue showed reduced cardiac hypertrophy, which was accompanied by diminished cardiac fibrosis and steatosis [58] (Table 1). ATX silencing in WAT resulted in a drastic decline in ATX levels in adipose tissue, serum, and cardiac tissue, as well as reduced circulating LPA levels [58].…”

Section: Studies Using Pharmacological Lpa Receptor and Atx Modulators And In Situ Atx Silencingmentioning

confidence: 72%

“…ATX mRNA levels in intra-abdominal adipose tissue were also higher in obese women with impaired glucose tolerance or diabetes than women with normal glucose tolerance [55]. Most, but not all, studies using mice with high fat diet-induced obesity demonstrate ATX upregulation, either through increased ATX expression in adipose tissue or circulating ATX protein/activity [18,33,35,[55][56][57][58][59][60]. Similarly, ATX mRNA levels were increased in adipose tissue from obese-diabetic db/db mice but not gold-thioglucose-treated mice [55].…”

Section: Regulation Of Atx and Lpp3 In The Context Of Obesity And Metabolic Diseasementioning

confidence: 99%

“…ATX silencing in WAT resulted in a drastic decline in ATX levels in adipose tissue, serum, and cardiac tissue, as well as reduced circulating LPA levels [58]. These changes were not accompanied by alterations in body weight [58]. High fat diet feeding induced a time-dependent increase in cardiac ATX levels and ATX levels correlated inversely with systolic function parameters, ejection fraction, and fractional shortening [58].…”

Section: Studies Using Pharmacological Lpa Receptor and Atx Modulators And In Situ Atx Silencingmentioning

confidence: 99%

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Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Jose

Kienesberger

2021

IJMS

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Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.

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Section: Studies Using Pharmacological Lpa Receptor and Atx Modulators And In Situ Atx Silencingsupporting

confidence: 64%

Section: Studies Using Pharmacological Lpa Receptor and Atx Modulators And In Situ Atx Silencingmentioning

confidence: 72%

Section: Regulation Of Atx and Lpp3 In The Context Of Obesity And Metabolic Diseasementioning

confidence: 99%

Section: Studies Using Pharmacological Lpa Receptor and Atx Modulators And In Situ Atx Silencingmentioning

confidence: 99%

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Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Jose

Kienesberger

2021

IJMS

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“…In mice fed HFD, autotaxin accumulation was associated with cardiac dysfunction in obese mice. On the other hand, autotaxin blockade protected obese mice against structural cardiac disorders, hypertrophy, and LV dysfunction [32].…”

Section: Effects Of Adipokines In Cvdmentioning

confidence: 98%

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Gutiérrez–Cuevas

Sandoval-Rodríguez

Meza-Ríos

et al. 2021

Cells

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Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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Serum autotaxin as a novel prognostic marker in patients with non‐ischaemic dilated cardiomyopathy

et al. 2022

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Aims Autotaxin (ATX) promotes myocardial inflammation, fibrosis, and the subsequent cardiac remodelling through lysophosphatidic acid production. However, the prognostic impact of serum ATX in non-ischaemic dilated cardiomyopathy (NIDCM) has not been clarified. We investigated the prognostic impact of serum ATX in patients with NIDCM. Methods and resultsWe enrolled 104 patients with NIDCM (49.8 ± 13.4 years, 76 men). We divided the patients into two groups using different cutoffs of median serum ATX levels for men and women: high-ATX group and low-ATX group. Cardiac events were defined as a composite of cardiac death and heart failure resulting in hospitalization. Median ATX level was 203.5 ng/mL for men and 257.0 ng/mL for women. Brain natriuretic peptide levels [224.0 (59.6-689.5) pg/mL vs. 96.5 (40.8-191.5) pg/mL, P = 0.010] were higher in the high-ATX group than low-ATX group, whereas high-sensitivity C-reactive protein and collagen volume fraction levels in endomyocardial biopsy samples were not significantly different between the two groups. Kaplan-Meier survival analysis revealed that the event-free survival rate was significantly lower in the high-ATX group than low-ATX group (log-rank; P = 0.007). Cox proportional hazard analysis revealed that high-ATX was an independent determinant of composite cardiac events. In both sexes, serum ATX levels did not correlate with high-sensitivity C-reactive protein levels and collagen volume fraction but had a weak correlation with brain natriuretic peptide levels (men; spearman's rank: 0.274, P = 0.017, women; spearman's rank: 0.378, P = 0.048). Conclusion High serum ATX levels can be associated with increasing adverse clinical outcomes in patients with NIDCM. These results indicate serum ATX may be a novel biomarker or therapeutic target in NIDCM.

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Adipose tissue-derived autotaxin causes cardiomyopathy in obese mice

Cited by 10 publications

References 37 publications

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Serum autotaxin as a novel prognostic marker in patients with non‐ischaemic dilated cardiomyopathy

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