Prevalence of elevated serum fatty acid synthase in chronic limb-threatening ischemia

Tay, Shirli; Silva, Gayan S. De; Engel, Connor; Harroun, Nikolai; Penrose, Amanda; Desai, Kshitij; Yan, Yan; Semenkovich, Clay F.; Zayed, Mohamed A.

doi:10.1038/s41598-021-98479-7

Cited by 3 publications

(5 citation statements)

References 32 publications

(35 reference statements)

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“…Our study observed different gene expression patters of ppara, acox1, and cpt1a in carotid and lower extremity arterial tissue, suggesting that atherosclerotic disease progression is unlikely homogeneous. We similarly observed that other critical lipid mediators are differentially expressed and activated in carotid and lower extremity arterial tissue (23,46,47). For example, choline-ethanolamine phosphotransferase 1 (CEPT1), a key regulator of de novo phospholipogenesis, is highly expressed in Min-diseased carotid arterial segments particularly in individuals with diabetes (22).…”

Section: Discussionmentioning

confidence: 80%

Altered Peroxisome Proliferator-Activated Receptor Alpha Signaling in Variably Diseased Peripheral Arterial Segments

Engel

Meade

Harroun

et al. 2022

Front. Cardiovasc. Med.

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ObjectivePeripheral atherosclerosis that accumulates in the extracranial carotid and lower extremity arteries can lead to significant morbidity and mortality. However, atherosclerotic disease progression is often not homogenous and is accelerated by diabetes. We previously observed increased phospholipid content in minimally (Min)-diseased arterial segments compared to maximally (Max)-diseased segments. Since Peroxisome Proliferator-Activated Receptor alpha (PPARα) is a key regulator of lipid metabolism, we hypothesized that it may have differential expression and signaling in Min vs. Max-diseased peripheral arterial segments.MethodsEighteen patients who underwent carotid endarterectomy (CEA), and 34 patients who underwent major lower extremity amputation were prospectively enrolled into a vascular tissue biobank. Min and Max-diseased segments were obtained in real-time from CEA plaque and amputated lower extremity arterial segments. mRNA and protein were isolated from specimens and the relative expression of ppara, and its downstream genes Acyl-CoA Oxidase 1 (acox1) and Carnitine Palmitoyltransferase 1A (cpt1a) were also evaluated. We evaluated gene expression and protein content relative to atherosclerotic disease severity and clinical diabetes status. Gene expression was also evaluated relative to Hemoglobin A1c and serum lipid profiles.ResultsIn CEA segments of patients with diabetes, we observed significantly higher ppara and acox1 gene expression (p < 0.01 and p < 0.001 respectively), and higher PPARα protein content (p < 0.05). Hemoglobin A1c significantly correlated with expression of ppara (R2 = 0.66, p < 0.001), acox1 (R2 = 0.31, p < 0.05), and cpt1a (R2 = 0.4, p < 0.05). There was no significant difference in gene expression between Min vs. Max-diseased CEA plaque segments. Conversely, in lower extremity arterial segments of patients with diabetes, we observed significantly lower ppara, acox1, and cpt1a expression (p < 0.05, p < 0.001, and p < 0.0001 respectively). Interestingly, CPT1A content was lower in arterial segments of patients with diabetes (p < 0.05). Hemoglobin A1c and HDL-cholesterol had negative correlations with ppara (R2 = 0.44, p < 0.05; R2 = 0.42, p < 0.05; respectively).ConclusionThis study demonstrates the significant differential expression of ppara and its immediate downstream genes in human carotid and lower extremity arteries relative to disease severity and diabetes. These findings highlight that mechanisms that influence atheroprogression in the carotid and lower extremities peripheral arteries are not homogenous and can be impacted by patient diabetes status and serum cholesterol profiles. Further elucidating these differential molecular mechanisms can help improve targeted therapy of atherosclerosis in different peripheral arterial beds.

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Section: Discussionmentioning

confidence: 80%

Altered Peroxisome Proliferator-Activated Receptor Alpha Signaling in Variably Diseased Peripheral Arterial Segments

Engel

Meade

Harroun

et al. 2022

Front. Cardiovasc. Med.

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“…Naturally, we also observed serum samples that had very high LDL (>180 mg/dL), while others that had low LDL (<90 mg/dL). Since it was previously reported that there was no correlation between cFAS and LDL content in human serum, we intentionally evaluated the impact of human serum samples with either high and low cFAS or LDL 21 . Like others who demonstrated that LDL alone does not cause macrophage foam cell formation, we also observed that macrophages conditioned with serum containing high LDL, but low cFAS, did not lead to foam cell formation [52][53][54][55] .…”

Section: Discussionmentioning

confidence: 99%

“…Serum LDL content was determined by the Washington University in St. Louis Core Laboratory for Clinical Studies (CLCS), utilizing a N-Geneous® LDL cholesterol kit (Sekisui Diagnostics, #7120) using a Roche Cobas c501 analyzer. Serum cFAS content was determined using commercial ELISA according to manufacturer's instructions (Aviva, OKEH04869) 21,22,26 . Following conditioned media treatments, macrophages were also lysed with standard freeze thaw method in PBS and lysates were standardized to protein concentration using Bradford Protein Assay.…”

Section: Human Serummentioning

confidence: 99%

“…FAS enzyme activity was measured as previously described with some modi cations 21,22,26 . Liver and white adipose tissue were digested in mammalian cell lysis kit (Milipore Sigma, MCL-1KT), and homogenates were centrifuged at 5,000g for 5 min at 4°C.…”

Section: Fas Enzyme Activity and Content Assaymentioning

confidence: 99%

“…Tissue Fatty Acid Synthase (FAS) is an essential soluble 273kDa intracellular homodimeric enzyme that catalyzes the de novo synthesis of saturated fatty acid through the conversion of acetyl-CoA and malonyl-CoA into palmitate [18][19][20] . It was recently observed that both tissue FAS and serum circulating FAS (cFAS) are elevated in individuals a icted with severe atherosclerotic cardiovascular disease 21 .…”

Section: Introductionmentioning

confidence: 99%

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Targeting Fatty Acid Synthase Reduces Aortic Atherosclerosis and Inflammation

zayed,

Meade,

Engel

et al. 2024

Preprint

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Fatty acid synthase (FAS) is predominantly expressed in the liver and adipose tissue. It plays vital roles in de novo synthesis of saturated fatty acid and regulates insulin sensitivity. We previously demonstrated that serum circulating FAS (cFAS) is a clinical biomarker for advanced atherosclerosis, and that it is conjugated to low-density lipoproteins (LDL). However, it remains unknown whether cFAS can directly impact atheroprogression. To investigate this, we evaluated whether cFAS impacts macrophage foam cell formation – a important cellular process leading to atheroprogression. Macrophages exposed to human serum containing high levels of cFAS showed increased foam cell formation as compared to cells exposed to serum containing low levels of cFAS. This difference was not observed using serum containing either high or low LDL. Pharmacological inhibition of cFAS using Platensimycin (PTM) decreased foam cell formation in vitro. In Apoe−/− mice with normal FAS expression, administration of PTM over 16 weeks along with a high fat diet decreased cFAS activity and aortic atherosclerosis without affecting circulating total cholesterol. This effect was also seen in Apoe−/− mice with liver-specific deletion of hepatic FAS. Reductions in aortic root plaque were associated with decreased macrophage infiltration. These findings demonstrate that cFAS can impact arterial atheroprogression.

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