TY - JOUR
T1 - Circulating serum fatty acid synthase is elevated in patients with diabetes and carotid artery stenosis and is LDL-associated
AU - De Silva, Gayan S.
AU - Desai, Kshitij
AU - Darwech, Malik
AU - Naim, Uzma
AU - Jin, Xiaohua
AU - Adak, Sangeeta
AU - Harroun, Nikolai
AU - Sanchez, Luis A.
AU - Semenkovich, Clay F.
AU - Zayed, Mohamed A.
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/8
Y1 - 2019/8
N2 - Background and aims: Diabetes is an independent risk factor for carotid artery stenosis (CAS). Fatty acid synthase (FAS), an essential de novo lipogenesis enzyme, has increased activity in the setting of diabetes that leads to altered lipid metabolism. Circulating FAS (cFAS) was recently observed in the blood of patients with hyperinsulinemia and cancer. We thought to evaluate the origin of cFAS and its role in diabetes-associated CAS. Methods: Patients with diabetes and no diabetes, undergoing carotid endarterectomy (CEA) for CAS, were prospectively enrolled for collection of plaque and fasting serum. FPLC was used to purify lipoprotein fractions, and ELISA was used to quantify cFAS content and activity. Immunoprecipitation (IP) was used to evaluate the affinity of cFAS to LDL-ApoB. Results: Patients with CAS had higher cFAS activity (p < 0.01), and patients with diabetes had higher cFAS activity than patients with no diabetes (p < 0.05). cFAS activity correlated with serum glucose (p = 0.03, r2 = 0.35), and cFAS content trended with plaque FAS content (p = 0.06, r2 = 0.69). cFAS was predominantly in LDL cholesterol fractions of patients with CAS (p < 0.001), and IP of cFAS demonstrated pulldown of ApoB. Similar to patients with diabetes, db/db mice had highest levels of serum cFAS (p < 0.01), and fasL−/− (tissue-specific liver knockdown of FAS) mice had the lowest levels of cFAS (p < 0.001). Conclusions: Serum cFAS is higher in patients with diabetes and CAS, appears to originate from the liver, and is LDL cholesterol associated. We postulate that LDL may be serving as a carrier for cFAS that contributes to atheroprogression in carotid arteries of patients with diabetes.
AB - Background and aims: Diabetes is an independent risk factor for carotid artery stenosis (CAS). Fatty acid synthase (FAS), an essential de novo lipogenesis enzyme, has increased activity in the setting of diabetes that leads to altered lipid metabolism. Circulating FAS (cFAS) was recently observed in the blood of patients with hyperinsulinemia and cancer. We thought to evaluate the origin of cFAS and its role in diabetes-associated CAS. Methods: Patients with diabetes and no diabetes, undergoing carotid endarterectomy (CEA) for CAS, were prospectively enrolled for collection of plaque and fasting serum. FPLC was used to purify lipoprotein fractions, and ELISA was used to quantify cFAS content and activity. Immunoprecipitation (IP) was used to evaluate the affinity of cFAS to LDL-ApoB. Results: Patients with CAS had higher cFAS activity (p < 0.01), and patients with diabetes had higher cFAS activity than patients with no diabetes (p < 0.05). cFAS activity correlated with serum glucose (p = 0.03, r2 = 0.35), and cFAS content trended with plaque FAS content (p = 0.06, r2 = 0.69). cFAS was predominantly in LDL cholesterol fractions of patients with CAS (p < 0.001), and IP of cFAS demonstrated pulldown of ApoB. Similar to patients with diabetes, db/db mice had highest levels of serum cFAS (p < 0.01), and fasL−/− (tissue-specific liver knockdown of FAS) mice had the lowest levels of cFAS (p < 0.001). Conclusions: Serum cFAS is higher in patients with diabetes and CAS, appears to originate from the liver, and is LDL cholesterol associated. We postulate that LDL may be serving as a carrier for cFAS that contributes to atheroprogression in carotid arteries of patients with diabetes.
KW - Carotid artery stenosis
KW - Diabetes
KW - Fatty acid synthase
KW - Lipoprotein
KW - Serum biomarker
UR - http://www.scopus.com/inward/record.url?scp=85067005435&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2019.05.016
DO - 10.1016/j.atherosclerosis.2019.05.016
M3 - Article
C2 - 31202106
AN - SCOPUS:85067005435
SN - 0021-9150
VL - 287
SP - 38
EP - 45
JO - Atherosclerosis
JF - Atherosclerosis
ER -