Fasting Serum Non-esterified Fatty Acid Research Articles

Serum Fasting Non-esterified Fatty Acids and Carotid Artery Intima-Media Thickness in Older Adults: The Cardiovascular Health Study

ObjectivesCarotid artery intima-media thickness (CIMT) has been used as an early indicator of subclinical atherosclerosis. Multiple studies have identified significant associations between plasma total non-esterified fatty acid (NEFA) concentrations and risk factors associated with subclinical atherosclerosis. However, the relationship between CIMT and serum NEFA is less clear. We hypothesized fasting serum total, individual saturated, and trans NEFA are positively associated with, and individual monounsaturated, n-6 polyunsaturated (PUFA) and n-3 PUFA NEFA are inversely associated with, CIMT. MethodsWe investigated the associations between fasting serum NEFA, and CIMT assessed in 1998–1999 among Cardiovascular Health Study (CHS) participants (N = 1,569) not taking anti-diabetic medication. A total of 35 individual NEFAs were measured in stored specimens from 1996–1997 using gas chromatography. CIMT was determined using ultrasound images, and was defined as the sum of the maximum common CIMT at the far wall divided by its standard deviation (SD) and the maximum internal CIMT at the far wall divided by its SD. At baseline, mean age was 77.3 ± 4.2, body mass index (BMI) was 26.8 ± 4.3 and 64% were female. Associations were assessed by linear regression, with adjustments for other individual NEFAs, age, sex, race, field center, education, smoking, BMI, physical activity, alcohol consumption, eGFR, serum albumin, hyperglycemia, hypertension, use of anti-hypertensive, statin, and other lipid-lowering drugs. ResultsIn adjusted models per SD increment, linoelaidic acid (trans18:2) was positively associated with CIMT [β (95% confidence interval): 10.4 (0.99, 19.8), P = 0.03], and α-linolenic acid (18:3n-3) was marginally associated with lower CIMT [–21.2 (–42.6, 0.2), P = 0.05]. No significant associations were observed between total NEFAs or any other individual NEFAs (SFA, MUFA, and n-6 PUFA) and CIMT. ConclusionsIn this large community-based cohort of older adults, higher concentration of linoelaidic acid was positively associated with CIMT, suggesting the importance of partially hydrogenated fat in the development of subclinical atherosclerosis in older adults. Overall, however, serum fasting NEFAs were largely unrelated to subclinical atherosclerosis in CHS participants. Funding SourcesNIH, NHLBI, USDA.

The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism.

Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wild-type (+/+) and knockout (−/−) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16 h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of apolipoprotein-A1 mRNA and decreased sterol regulatory element-binding protein 1 mRNA independent of genotype, suggesting a possible GPR109a independent mechanism by which niacin increases high-density lipoprotein (HDL) production and limits transcriptional upregulation of lipogenic genes. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and −/− mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator-activated receptor α mRNA expression. Although unaffected by niacin treatment, fasting serum HDL concentrations were lower in GPR109a knockout mice. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the fasting ketogenic state or the acute effects of niacin.

The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue.

The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3148MM/MI , n = 63; PNPLA3148II , n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3148MM , n = 25) or lacking the variant (PNPLA3148II , n = 25). Whole-body insulin sensitivity of lipolysis was determined using [2 H5 ]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P < .0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P < .0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P < .0001). Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.

Cognitive impairment in elderly patients with type 2 diabetes mellitus: prevalence and related clinical factors.

Diabetes mellitus is reported to be a risk factor for dementia. We evaluated the cognitive function in elderly diabetic patients and estimated the prevalence of patients with cognitive impairment and looked for any related clinical factors. Using 281 elderly (65years of age or older) Japanese patients with type 2 diabetes mellitus who were free of clinically evident cognitive impairment, we evaluated their cognitive function with the Mini Mental State Examination (MMSE). The MMSE score of all the participants was 27.3±2.4 with 31.3% of them being in the abnormal range (tentatively defined normal range as having an MMSE score of 27-30). Multiple regression analysis disclosed that fasting serum non-esterified fatty acid (NEFA), estimated glomerular filtration ratio (eGFR) and insulin treatment were significantly related factors for the MMSE score, in addition to age and schooling history, which are extremely strong factors. We revealed that approximately one-third of elderly type 2 diabetic patients who were free of clinically evident cognitive impairment had impaired cognitive function, demonstrating that the MMSE score was significantly correlated with fasting NEFA level, renal function, insulin treatment, age and schooling history.

Lactobacillus gasseri SBT2055 reduces postprandial and fasting serum non-esterified fatty acid levels in Japanese hypertriacylglycerolemic subjects

BackgroundLactobacillus gasseri SBT2055 (LG2055) inhibits dietary fat absorption in rats and exerts preventive effects on abdominal adiposity in rats and humans. The present study aimed to evaluate the effects of LG2055 on postprandial serum lipid responses in Japanese subjects with hypertriacylglycerolemia after the intake of oral fat-loading test (OFLT) meals.MethodsWe conducted a single-blind, placebo-controlled, within-subject, repeated-measure intervention trial. Twenty subjects initially ingested the fermented milk (FM) without LG2055 for 4 weeks (control FM period), followed by a 4-week washout period, and then consumed FM containing LG2055 for 4 weeks (active FM period). The subjects were asked to consume FM at 200 g/day. At the end of each 4-week period, an 8-h OFLT was conducted. Blood samples were collected at fasting and every hour for 8 h after OFLT meal intake. Thereafter, postprandial serum non-esterified fatty acid (NEFA) and triacylglycerol (TAG) levels and fasting blood parameters were measured.ResultsThe OFLT showed that the postprandial serum NEFA levels from 120 to 480 min and the postprandial serum TAG level at 120 min in the active FM period were significantly (P < 0.05) lower than those in the control FM period. The fasting serum NEFA level in the active FM period significantly (P < 0.001) decreased at week 4 from the initial period compared with the control FM period.ConclusionsThe consumption of probiotic LG2055 reduced postprandial and fasting serum NEFA levels, suggesting its possible contribution to the reduction of the risk for obesity and type 2 diabetes mellitus.Trial registrationUMIN000011605

Non-esterified fatty acid is being validated as a substitute measure for non-protein respiratory quotient in patients with cirrhosis

Summary Background & aims A late evening snack (LES) is recommended for improving starvation state in cirrhotic patients. The non-protein respiratory quotient (npRQ) is an important index for evaluating the indications and effectiveness of LES. Indirect calorimetry is used to determine npRQ, but it is expensive and not available in many hospitals. The aim was to find blood biochemical markers reflecting npRQ. Methods A total of 183 cirrhotic patients (M/F = 149/34) were enrolled. For each patient, fasting state npRQ was determined by indirect calorimetry. The relationships between npRQ and indices such as age, body mass index, platelet count, etiology, and levels of aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, blood glucose, and non-esterified fatty acid (NEFA) were statistically analyzed. Results There was a significant negative correlation between the measured npRQ and serum NEFA levels, and the NEFA level was the strongest predictor of npRQ. Multiple regression analysis identified that the NEFA and Hepatitis B virus were predictors of npRQ. Conclusion These data suggest that fasting serum NEFA level is the most relevant biomarker to determine npRQ if indirect calorimetry is unavailable. Thus, serum NEFA levels may be useful to determine the indications and effectiveness of LES therapy in cirrhotic patients.

Effect of exposure to non‐esterified fatty acid on progressive deterioration of insulin secretion in patients with Type 2 diabetes: a long‐term follow‐up study

The aim of the study was to determine whether fasting serum non-esterified fatty acid (NEFA) could be associated with long-term progressive deterioration of insulin secretion in patients with Type 2 diabetes. Seventy-seven Japanese patients with Type 2 diabetes (mean BMI 23.3 kg/m(2) ) were followed for 10 years. We measured fasting C-peptide level every 1-2 years. By using the slope of regression line between fasting C-peptide level and duration, we calculated its individual annual decline as an index of insulin secretion. During the follow-up periods of C-peptide, the patients were evaluated for fasting serum non-esterified fatty acid, LDL cholesterol, HDL cholesterol and HbA(1c) levels for the last 8 years. We excluded patients who had renal dysfunction or anti-insulin antibodies from among the insulin-treated patients. Association between the individual annual decline of fasting C-peptide level and related factors were evaluated. The mean individual annual decline of fasting serum C-peptide level was -0.013 ± 0.027 nmol/l/year. Fasting serum non-esterified fatty acid level had no significant difference between the first and the last 2 years of the 8-year observation period of non-esterified fatty acid. Using multiple regression analysis, mean fasting serum non-esterified fatty acid level was associated with the individual annual decline of fasting serum C-peptide level (standardized regression coefficient -0.358, P=0.0056), although other related factors, including HbA(1c) level, were not associated. Mean fasting serum non-esterified fatty acid level during an 8-year observation was independently associated with long-term progressive deterioration of insulin secretion in Japanese patients with Type 2 diabetes.

Investigation of in vivo fatty acid metabolism in AFABP/aP2(-/-) mice.

The metabolic impact of the murine adipocyte fatty acid-binding protein (AFABP/aP2) on lipid metabolism was investigated in the AFABP/aP2(-/-) mouse and compared with wild-type C57BL/6J littermates. Mice were weaned on a high-fat diet (59% of energy from fat) and acclimated to meal feeding. Stable isotopes were administered, and indirect calorimetry was performed to quantitate fatty acid flux, dietary fatty acid utilization, and substrate oxidation. Consistent with previous in situ and in vitro studies, fasting serum nonesterified fatty acid (NEFA) release was significantly reduced in AFABP/aP2(-/-) (17.1 +/- 9.0 vs. 51.9 +/- 22.9 mg.kg(-1).min(-1)). AFABP/aP2(-/-) exhibited higher serum NEFA (1.4 +/- 0.6 vs. 0.8 +/- 0.4 mmol/l, AFABP/aP2(-/-) vs. C57BL/6J, respectively) and triacylglycerol (TAG; 0.23 +/- 0.09 vs. 0.13 +/- 0.10 mmol/l) and accumulated more TAG in liver tissue (2.9 +/- 2.3 vs. 1.1 +/- 0.8% wet wt) in the fasted state. For the liver-TAG pool, 16.4 +/- 7.3% of TAG-fatty acids were derived from serum NEFA in AFABP/aP2(-/-). In contrast, a significantly greater portion of C57BL/6J liver-TAG was derived from serum NEFA (42.3 +/- 25.5%) during tracer infusion. For adipose-TAG stores, only 0.29 +/- 0.04% was derived from serum NEFA in AFABP/aP2(-/-), and, in C57BL/6J, 1.85 +/- 0.97% of adipose-TAG was derived from NEFA. In addition, AFABP/aP2(-/-) preferentially oxidized glucose relative to fatty acids in the fed state. These data demonstrate that in vivo disruption of AFABP/aP2(-/-) leads to changes in the following two major metabolic processes: 1) decreased adipose NEFA efflux and 2) preferential utilization of glucose relative to fatty acids.

Serum non-esterified very long-chain PUFA are associated with markers of endothelial dysfunction

The objective of this study was to investigate the pattern of serum non-esterified fatty acid (NEFA) fraction in association with atherosclerosis development. We have studied possible relationships between eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) in the NEFA fraction and biochemical markers of endothelial activation or dysfunction. The study population consisted of 152 elderly men with high risk for coronary heart disease. The composition of fasting serum NEFA was analysed by gas–liquid chromatography. Endothelial activation was evaluated using biochemical analyses of some markers of endothelial function. A significant inverse linear association was found between serum non-esterified EPA and DHA, and soluble vascular cell adhesion molecule-1 (sVCAM-1) ( P=0.02 and 0.001, respectively). An inverse linear association was found between serum non-esterified AA and sVCAM-1 ( P=0.001) and von Willebrand Factor ( P=0.005). The significant inverse associations for DHA and AA were independent from the serum content of other NEFAs. Taken together, negative associations were found between sVCAM-1 and the serum levels of non-esterified DHA, EPA and AA. The inverse relation between the levels of sVCAM-1 and very long-chain n-3 fatty acids might indicate an anti-inflammatory effect of the latter.

Lipid metabolism and substrate oxidation during intravenous fructose administration in cirrhosis

We used isotope dilution techniques (constant intravenous [IV] infusion of 2- 3H-glycerol and 1- 14C-palmitate) and indirect calorimetry to measure lipid kinetics and substrate oxidation rates during IV fructose administration at 200 and then 500 mg/kg/h in eight cirrhotic patients and seven normal control subjects. Fasting plasma glucose, glycerol, and glycerol appearance rate (R a) were similar in both groups, but insulin levels were fourfold higher in cirrhotics ( P < .01). Fasting serum nonesterified fatty acid (NEFA) levels (cirrhotics, 869 ± 124, controls, 717 ± 90 μmol/L) and NEFA R a (7.1 ± 0.8 v 5.5 ± 0.9 μmol/min/kg) were higher in cirrhotics, but the differences were not significant. Plasma fructose was similar in both groups at both fructose infusion rates. Fructose appeared to stimulate insulin secretion. With IV fructose, serum NEFA levels decreased, reaching similar low levels when 500 mg/kg/h was infused, due to a reduction in NEFA R a and an increase in the NEFA metabolic clearance rate (MCR). Glycerol levels showed little change. As glycerol R a decreased by less than 20% in both groups, the decrease in serum NEFA was primarily due to enhanced reesterification of fatty acids both within adipose tissue (preventing their release) and in other tissues (enhancing their removal from plasma). Although total fructose utilization was normal in cirrhotics, they oxidized more of the infused fructose; nonoxidative disposal was reduced (first step, 242 ± 12 v 318 ± 16 mg/kg in 2 hours, P < .002; second step, 657 ± 32 v 786 ± 21 mg/kg in 2 hours, P < .005). Although tissue fructose uptake is insulin-independent, insulin resistance in cirrhosis may influence the intracellular metabolism of fructose.

Effect of a diabetogeic factor from bovine adenohypophysis on dog serum nefa levels

1. 1. Fasted dog serum non-esterified fatty acid (NEFA) levels were elevated 10 and 34 hours after administration of a diabetogenic protein (BDF) isolated from bovine adenohypophysis. 2. 2. The fasting serum NEFA were elevated in spite of the presence of normal or high glucose and insulin levels. 3. 3. After oral glucose administration to BDF-treated animals, a fall of serum NEFA paralleled inversely the increasing levels of blood glucose and serum insulin. 4. 4. These data are discussed with respect to the insulin-antagonistic action of BDF. Even though the plasma NEFA fell in response to glucose in BDF-treated animals, the NEFA during the entire 3-hour glucose-tolerance test were always significantly higher than the levels observed in the control tests. 5. 5. Since BDF is similar to the diabetogenic protein isolated from the urine of patients with lipoatrophic diabetes, its lipid-mobilizing action might help to explain the lipoatrophy, hyperlipaemia, diabetes mellitus, and insulin resistance seen in lipoatrophic diabetic patients.