Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 and angiopoietin-like protein 4 are associated with the increase of lipoprotein lipase activity in epicardial adipose tissue from diabetic patients

OBJECTIVE: Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. APPROACH AND RESULTS: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10 −4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02). CONCLUSIONS: CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.

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“…15 Purity of lipoproteins was tested by agarose gel electrophoresis, as previously described. 16 Determination of Lipidomic Profile…”

Section: Vldl and Hdl Isolationmentioning

confidence: 99%

Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease

Barchuk

Dutour

Ancel

et al. 2020

ATVB

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“…LPL is mainly post-translationally regulated, 11 and its activity is reduced in insulin-resistant states. 12,13 Paradoxically, we have demonstrated that LPL activity is increased in EAT from CAD compared to non-CAD diabetic patients 10 ; suggesting that LPL could be implicated in EAT expansion.…”

mentioning

confidence: 83%

“…EAT and SAT were homogenized as previously described. 10 Tissue homogenates were centrifuged and protein concentrations were determined by Lowry method in the supernatant. 25…”

Section: Lpl Regulators Expressionmentioning

confidence: 99%

“…9 Among the main actors involved in the FA influx to the tissue, it is worth mentioning that VLDL-R (very low-density lipoprotein receptor) and LPL (lipoprotein lipase) have probably a central role. Previous results from our laboratory showed that VLDL-R expression is higher in EAT compared to SAT in patients with coronary artery disease (CAD), 10 suggesting an active role in the uptake of FA from circulating lipoproteins. Besides, LPL activity would also contribute to the uptake of FA, hydrolyzing triglycerides from VLDL, and chylomicrons.…”

mentioning

confidence: 93%

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Epicardial Adipose Tissue Ceramides Are Related to Lipoprotein Lipase Activity in Coronary Artery Disease: Unfolding a Missing Link

Barchuk

Ancel

Miksztowicz

et al. 2022

ATVB

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Background: Epicardial adipose tissue (EAT) contributes to coronary artery disease (CAD). EAT presents a specific lipidomic signature, showing increased ceramides and other proinflammatory lipids content. Besides, LPL (lipoprotein lipase) activity in EAT would contribute to its expansion, supplying fatty acids to the tissue. Our aim was to evaluate the relations between LPL activity, regulators of LPL, and ceramides in EAT from CAD patients. Methods: We studied patients undergoing coronary bypass graft (CAD, n=25) and patients without CAD (no CAD, n=14). EAT and subcutaneous AT (SAT) were obtained, tissue LPL activity and its regulator’s expression (ANGPTL4, GPIHBP1 [glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1], and PPARγ [peroxisomal proliferator–activated receptor γ]) were assessed. Tissue lipidomes were evaluated by UHPLC-MS, in positive and negative ionization modes. Results: LPL activity was higher in EAT from CAD ( P <0.001), and in EAT than SAT in both groups ( P <0.001). ANGPTL4 levels were lower, GPIHBP1 and PPARγ levels were higher in EAT from CAD ( P <0.001). In both groups, EAT exhibited more ceramide ( P =0.01), directly associated with LPL activity, being the strongest association with Cer18:1/24:1 ( P <0.001). EAT Cer18:1/16:0 to Cer18:1/24:0 and Cer18:1/24:1 to 18:1/24:0 ratios were higher in CAD ( P =0.03; P <0.001, respectively), the latter directly associated with LPL activity ( r =0.63, P <0.001) GPIHBP1 levels ( r =0.68, P <0.001), and inversely to EAT ANGPTL4 expression ( r =−0.49, P =0.03). Pairwise partial correlation network showed associations among bioactive lipids and LPL and its regulators ( P <0.001 in all cases). Conclusions: The association between LPL activity, total ceramide, and the atherogenic ceramide ratios highlights the importance of the enzyme and these bioactive lipids contributing to the different metabolic profile of EAT in CAD.

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“…ANGPTL4 is known to inactivate LPL, which reduces triglycerides (TG) conversion to free fatty acids, leading to hypertriglyceridemia (Sukonina et al, 2006;Mattijssen & Kersten, 2012). Additionally, ANGPTL4 is associated with increased plasma TG (Barchuk et al, 2019;Gao et al, 2019). To identify whether elevated plasma TG by ANGPTL4 is a key risk factor in pancreatitis, we evaluated TG levels in pancreatitis patients (n = 80) compared with those of normal subjects.…”

Section: Association Of Angptl4 With Tg or Ppar-cmentioning

confidence: 99%

ANGPTL 4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a

et al. 2020

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Pancreatitis is the inflammation of the pancreas. However, little is known about the genes associated with pancreatitis severity. Our microarray analysis of pancreatic tissues from mild and severe acute pancreatitis mice models identified angiopoietin‐like 4 ( ANGPTL 4) as one of the most significantly upregulated genes. Clinically, ANGPTL 4 expression was also increased in the serum and pancreatic tissues of pancreatitis patients. The deficiency in ANGPTL 4 in mice, either by gene deletion or neutralizing antibody, mitigated pancreatitis‐associated pathological outcomes. Conversely, exogenous ANGPTL 4 exacerbated pancreatic injury with elevated cytokine levels and apoptotic cell death. High ANGPTL 4 enhanced macrophage activation and infiltration into the pancreas, which increased complement component 5a (C5a) level through PI 3K/ AKT signaling. The activation of the C5a receptor led to hypercytokinemia that accelerated acinar cell damage and furthered pancreatitis. Indeed, C5a neutralizing antibody decreased inflammatory response in LPS ‐activated macrophages and alleviated pancreatitis severity. In agreement, there was a significant positive correlation between C5a and ANGPTL 4 levels in pancreatitis patients. Taken together, our study suggests that targeting ANGPTL 4 is a potential strategy for the treatment of pancreatitis.

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Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 and angiopoietin-like protein 4 are associated with the increase of lipoprotein lipase activity in epicardial adipose tissue from diabetic patients

Cited by 12 publications

References 40 publications

Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease

Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease

Epicardial Adipose Tissue Ceramides Are Related to Lipoprotein Lipase Activity in Coronary Artery Disease: Unfolding a Missing Link

ANGPTL 4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a

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