Relation of Plasma Fatty Acid Binding Proteins 4 and 5 With the Metabolic Syndrome, Inflammation and Coronary Calcium in Patients With Type-2 Diabetes Mellitus

Bagheri, Roshanak; Qasim, Atif; Mehta, Nehal N.; Terembula, Karen; Kapoor, Shiv; Braunstein, Seth; Schutta, Mark; Iqbal, Nayyar; Lehrke, Michael; Reilly, Muredach P.

doi:10.1016/j.amjcard.2010.06.028

Cited by 67 publications

(61 citation statements)

References 27 publications

(40 reference statements)

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“…Recent studies have established that upregulation of hepatic CD36 is associated with insulin resistance and hepatic steatosis in humans (29), and alterations in NEFA uptake regulated at the level of fatty acid transporter CD36 expression are thought to be involved in increased TG accumulation in patients with NAFLD (17). In addition, the role of intracellular fatty acid-binding proteins such as FABP5 in the metabolic syndrome and/or diabetes is also established by several studies (3,8). However, in mouse models with disrupted leptin signaling, such ob/ob or db/db mice, fatty acid uptake does not play a causal role in hepatic steatosis (16).…”

Section: Discussionmentioning

confidence: 99%

Macrophage-specific transgenic expression of cholesteryl ester hydrolase attenuates hepatic lipid accumulation and also improves glucose tolerance in ob/ob mice

Bie

Zhao

Marqueen

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Macrophage-specific transgenic expression of cholesteryl ester hydrolase attenuates hepatic lipid accumulation and also improves glucose tolerance in ob/ob mice. Am J Physiol Endocrinol Metab 302: E1283-E1291, 2012. First published March 6, 2012; doi:10.1152/ajpendo.00511.2011.-Cellular cholesterol homeostasis is increasingly being recognized as an important determinant of the inflammatory status of macrophages, and a decrease in cellular cholesterol levels polarizes macrophages toward an anti-inflammatory or M2 phenotype. Cholesteryl ester hydrolase (CEH) catalyzes the hydrolysis of stored intracellular cholesteryl esters (CE) and thereby enhances free cholesterol efflux and reduces cellular CE content. We have reported earlier reduced atherosclerosis as well as lesion necrosis and improved insulin sensitivity (due to decreased adipose tissue inflammation) in macrophage-specific CEH transgenic (CEHTg) mice in the LDLR Ϫ/Ϫ background. In the present study, we examined the effects of reduced intracellular accumulation of CE in CEHTg macrophages in an established diabetic mouse model, namely the leptin-deficient ob/ob mouse. Macrophage-specific transgenic expression of CEH improved glucose tolerance in ob/obCEHTg mice significantly compared with ob/ob nontransgenic littermates, but with no apparent change in macrophage infiltration into the adipose tissue. However, there was a significant decrease in hepatic lipid accumulation in ob/ob-CEHTg mice. Consistently, decreased [ 14 C]acetate incorporation into total lipids and triglycerides was noted in precision-cut liver slices from ob/ob-CEHTg mice. In the primary hepatocyte-macrophage coculture system, macrophages from CEHTg mice significantly reduced the incorporation of [ 14 C]acetate into triglycerides in hepatocytes, indicating a direct effect of macrophages on hepatocyte triglyceride biosynthesis. Kupffer cells isolated from ob/ob-CEHTg mice were polarized toward an anti-inflammatory M2 (Ly6C lo ) phenotype. Taken together, these studies demonstrate that transgenic overexpression of CEH in macrophages polarizes hepatic macrophages (Kupffer cells) to an anti-inflammatory M2 phenotype that attenuates hepatic lipid synthesis and accumulation. macrophage phenotype and inflammatory status; cell-to-cell interaction; coculture MACROPHAGE CHOLESTEROL HOMEOSTASIS is central to foam cell formation and development of atherosclerotic plaques. Although contribution of macrophage foam cells to the growing lipid core of the plaque is well established, the role of these foam cells in regulating plaque-associated inflammation is increasingly being recognized. The increase in intracellular cholesteryl esters (CE) within macrophages is an important determinant of the inflammatory status of macrophages, and Fazio and Linton (14) proposed a feedback loop where defects in cellular cholesterol balance induced changes in production of inflammatory mediators. Consistently, an increase in cellular cholesterol content by deficiency of cholesterol transporter ATP-binding cassette transpor...

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Section: Discussionmentioning

confidence: 99%

Macrophage-specific transgenic expression of cholesteryl ester hydrolase attenuates hepatic lipid accumulation and also improves glucose tolerance in ob/ob mice

Bie

Zhao

Marqueen

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…23,24 It has to be noted that these conditions are associated with higher FABP4 levels, as found in this and other studies. 25,26 Secondly, circulating FABP4 was significantly elevated in patients with ACS who experienced adverse cerebrovascular or cardiovascular events within 30 days after the index ACS event. Furthermore, FABP4 showed the same prognostic power to predict adverse events as the GRACE in-hospital risk score or NT-proBNP.…”

Section: Discussionmentioning

confidence: 99%

Circulating FABP4 Is a Prognostic Biomarker in Patients With Acute Coronary Syndrome but Not in Asymptomatic Individuals

Reiser¹,

Klingenberg²,

Hof³

et al. 2015

ATVB

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Objective— Blood-borne biomarkers reflecting atherosclerotic plaque burden have great potential to improve clinical management of atherosclerotic coronary artery disease and acute coronary syndrome (ACS). Approach and Results— Using data integration from gene expression profiling of coronary thrombi versus peripheral blood mononuclear cells and proteomic analysis of atherosclerotic plaque–derived secretomes versus healthy tissue secretomes, we identified fatty acid–binding protein 4 (FABP4) as a biomarker candidate for coronary artery disease. Its diagnostic and prognostic performance was validated in 3 different clinical settings: (1) in a cross-sectional cohort of patients with stable coronary artery disease, ACS, and healthy individuals (n=820), (2) in a nested case–control cohort of patients with ACS with 30-day follow-up (n=200), and (3) in a population-based nested case–control cohort of asymptomatic individuals with 5-year follow-up (n=414). Circulating FABP4 was marginally higher in patients with ST-segment–elevation myocardial infarction (24.9 ng/mL) compared with controls (23.4 ng/mL; P =0.01). However, elevated FABP4 was associated with adverse secondary cerebrovascular or cardiovascular events during 30-day follow-up after index ACS, independent of age, sex, renal function, and body mass index (odds ratio, 1.7; 95% confidence interval, 1.1–2.5; P =0.02). Circulating FABP4 predicted adverse events with similar prognostic performance as the GRACE in-hospital risk score or N-terminal pro–brain natriuretic peptide. Finally, no significant difference between baseline FABP4 was found in asymptomatic individuals with or without coronary events during 5-year follow-up. Conclusions— Circulating FABP4 may prove useful as a prognostic biomarker in risk stratification of patients with ACS.

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“…We found a positive association between blood concentrations of FABP4 and indicators of abdominal fat, such as BMI and the area of fat (total abdominal, visceral, and subcutaneous). Studies have demonstrated that blood concentrations of FABP4 are positively associated with the prevalence of obesity, insulin resistance, T2DM and/or carotid atherosclerosis in Asian countries (6)(7)(8)24). Those studies, along with the present study, suggest that blood concentrations of FABP4 are positively associated with the prevalence of obesity in middle-aged Japanese males not taking medi- cations for metabolic diseases.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that injection of a chemical inhibitor of FABP4 into animals reduced the development of atherosclerosis (5). Cross-sectional studies demonstrated blood concentrations of FABP4 to be positively associated with obesity, insulin resistance, hypertension and carotid atherosclerosis in: 234 South Korean adults; 806 American patients with type-2 diabetes mellitus (T2DM); and 459 Chinese patients who had undergone coronary angiography (6)(7)(8). Furthermore, cohort studies demonstrated that blood concentrations of FABP4 in 495 non-T2DM subjects and 1,847 subjects without previous cardiovascular disease (CVD) in China were positively associated with subsequent metabolic syndrome (MetS) and carotid atherosclerosis (9,10).…”

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confidence: 99%

Serum Fatty Acid Binding Protein 4 Concentrations Are Positively and Independently Associated with Blood Pressure and Abdominal Fat among Parameters in Health Check-Ups in Ordinary Middle-Aged Japanese Males

Yamada

Mochizuki

Honma

et al. 2015

J Nutr Sci Vitaminol

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SummaryWe wished to examine potential associations among blood concentrations of fatty acid-binding protein (FABP) 4 and parameters in health check-ups such as abdominal fat area (AFA) and blood pressure (BP) in middle-aged Japanese males. We conducted a cross-sectional study of males who participated in health check-ups in Japan. We excluded participants diagnosed with metabolic diseases by the time of their check-up. A total of 305 subjects (30-64 [mean6standard deviation, 47.368.5] y) were recruited. Areas of totalabdominal, visceral and subcutaneous fat were measured using computed tomography. We compared the association of serum concentrations of FABP4 with various clinical parameters by Pearson product-moment correlation coefficient (PPMCC) analyses, and by stepwise multivariate linear regression analyses (MLRA). PPMCC analyses showed that blood concentrations of FABP4 were positively associated with: body mass index; areas of fat (total abdominal, visceral, subcutaneous); systolic BP; diastolic BP; total cholesterol; low-density lipoprotein-cholesterol; triacylglycerol; activities of g-glutamyl transpeptidase, aspartate aminotransferase and alanine aminotransferase; white blood cell count; and levels of creatinine.Step-wise MLRA showed that AFAs (visceral and subcutaneous) and diastolic BP were positively and independently associated with serum concentrations of FABP4 among the parameters tested. These data suggest that serum concentrations of FABP4 are independently and positively associated with BP and AFA among parameters measured in health check-ups in middle-aged Japanese males.

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Relation of Plasma Fatty Acid Binding Proteins 4 and 5 With the Metabolic Syndrome, Inflammation and Coronary Calcium in Patients With Type-2 Diabetes Mellitus

Cited by 67 publications

References 27 publications

Macrophage-specific transgenic expression of cholesteryl ester hydrolase attenuates hepatic lipid accumulation and also improves glucose tolerance in ob/ob mice

Macrophage-specific transgenic expression of cholesteryl ester hydrolase attenuates hepatic lipid accumulation and also improves glucose tolerance in ob/ob mice

Circulating FABP4 Is a Prognostic Biomarker in Patients With Acute Coronary Syndrome but Not in Asymptomatic Individuals

Serum Fatty Acid Binding Protein 4 Concentrations Are Positively and Independently Associated with Blood Pressure and Abdominal Fat among Parameters in Health Check-Ups in Ordinary Middle-Aged Japanese Males

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