Hyperlipidemia as a risk factor for cardiovascular disease.

Elevated levels of blood lipids are well-documented risk factors for cardiovascular disease. Current classification schemes and treatment levels for hyperlipidemia are based on the National Cholesterol Education Panel's Adult Treatment Program-3 (ATP-III) guidelines. Extensive research over the past decade has raised the question whether or not ATP-III guidelines are sufficiently aggressive. New guidelines from ATP-IV are expected to be released in the near future, but in the meantime physicians are faced with uncertainty about how low to target low-density lipoprotein cholesterol, whether to pharmacologically treat high-density lipoprotein cholesterol and triglyceride levels, and how best to achieve target goals.

Kinetics of saturated, monounsaturated, and polyunsaturated fatty acids in humans.

Plasma free fatty acid (FFA) kinetics in humans are often measured with only one tracer. In study 1, healthy volunteers received infusions of [U-¹³C]linoleate, [U-¹³C]oleate, and [U-¹³C]palmitate during continuous feeding with liquid meals low (n = 12) and high (n = 5) in palmitate and containing three labeled fatty acids to measure FFA appearance and fractional spillover of lipoprotein lipase-generated fatty acids. Study 2 used an intravenous lipid emulsion to increase FFA concentrations during infusion of linoleate and palmitate tracers. In study 1, there were no differences in spillover of the three fatty acids for the low-palmitate meal, but linoleate spillover was greater than oleate or palmitate for the high-palmitate meal. In studies 1 and 2, clearance was significantly greater for linoleate than for the other FFAs. There was a negative correlation between clearance and concentration for each fatty acid in the two studies. In study 1, concentration and spillover correlated positively for oleate and palmitate but negatively for linoleate. In conclusion, linoleate spillover is greater than that of other fatty acids under some circumstances. Linoleate clearance is greater than that of palmitate or oleate, indicating a need for caution when using a single FFA to infer the behavior of all fatty acids.

Spillover of Fatty acids during dietary fat storage in type 2 diabetes: relationship to body fat depots and effects of weight loss.

Spillover of lipoprotein lipase-generated fatty acids from chylomicrons into the plasma free fatty acid (FFA) pool is an important source of FFA and reflects inefficiency in dietary fat storage. We measured spillover in 13 people with type 2 diabetes using infusions of a [(3)H]triolein-labeled lipid emulsion and [U-(13)C]oleate during continuous feeding, before and after weight loss. Body fat was measured with dual energy X-ray absorptiometry and computed tomography. Participants lost ∼14% of body weight. There was an ∼38% decrease in meal-suppressed FFA concentration (P < 0.0001) and an ∼23% decrease in oleate flux (P = 0.007). Fractional spillover did not change (P = NS). At baseline, there was a strong negative correlation between spillover and leg fat (r = -0.79, P = 0.001) and a positive correlation with the trunk-to-leg fat ratio (R = 0.56, P = 0.047). These correlations disappeared after weight loss. Baseline leg fat (R = -0.61, P = 0.027) but not trunk fat (R = -0.27, P = 0.38) negatively predicted decreases in spillover with weight loss. These results indicate that spillover, a measure of inefficiency in dietary fat storage, is inversely associated with lower body fat in type 2 diabetes.

Effect of insulin infusion on spillover of meal-derived fatty acids.

CONTEXT: Spillover of chylomicron triglyceride fatty acids directly into the circulation as free fatty acids (FFAs) during lipoprotein lipase hydrolysis may contribute to the elevated total FFAs seen in insulin-resistant states. OBJECTIVE: The objective of the study was to determine whether spillover is regulated by rates of intracellular lipolysis, we studied overweight and obese nondiabetic subjects (n = 7) on two occasions, during infusion of saline and insulin. DESIGN: During insulin infusion (20 mU · m(-2) · min(-1)), plasma glucose was clamped at the concentration achieved during saline infusion. On both study days, subjects sipped 1-2 oz of a liquid mixed meal every 15 min for 6.5 h to achieve steady-state chylomicron and FFA concentrations. Spillover was measured with infusions of [(3)H]triolein and [U-(13)C] oleate. RESULTS: Glucose concentrations were similar during saline compared with insulin (113 ± 2 vs. 113 ± 1 mg/dl, P = NS). Insulin levels during saline and insulin infusion were 18 ± 3 and 44 ± 5 µU/ml, respectively. Glucose infusion rate during insulin infusion was 5.5 ± 1.0 mg · kg fat-free mass(-1) · min(-1). Plasma FFA concentrations were lower during insulin compared with saline (75 ± 8 vs. 124 ± 13 µmol/liter, P = 0.002). Oleate rate of appearance was lower during insulin vs. saline (27 ± 3 vs. 36 ± 5 µmol/min, P = 0.004). Spillover was similar during saline and insulin (26 ± 2 vs. 25 ± 2%, P = 0.60). CONCLUSIONS: These results indicate that suppression of intracellular lipolysis with insulin does not reduce lipoprotein lipase-mediated spillover in humans during meal absorption. It is possible that spillover did not decrease because of an impaired or absent antilipolytic effect of increased insulin concentrations in visceral fat.

Intravenous niacin acutely improves the efficiency of dietary fat storage in lean and obese humans.

Spillover of fatty acids released by lipoprotein lipase hydrolysis of meal triglycerides may be a major contributor to the free fatty acid (FFA) pool. We studied lean (n = 6) and overweight and obese (n = 5) subjects during continuous feeding on two occasions: during intravenous infusion of niacin (2.8 mg/min) and saline. After establishment of steady-state chylomicronemia and suppression of adipose tissue lipolysis with a liquid meal, spillover was measured with infusions of [U-(13)C]oleate and [(3)H]triolein. Total FFA concentrations were lower during niacin infusion in both lean (50 ± 4 vs. 102 ± 7 µmol/L; P < 0.002) and obese (75 ± 6 vs. 143 ± 13 µmol/L; P < 0.01) subjects. Oleate appearance was lower during niacin infusion than during saline infusion in both lean (21 ± 2 vs. 32 ± 5 µmol/min; P = 0.07) and obese subjects (25 ± 3 vs. 46 ± 8 µmol/min; P < 0.02). Spillover was lower during niacin infusion than during saline infusion in lean (21 ± 4 vs. 29 ± 3%) and obese (21 ± 2 vs. 29 ± 5%) subjects (P < 0.03 for both). In summary, during meal absorption, niacin produces additional suppression of lipolysis and a reduction in fractional spillover compared with saline in both normal and obese subjects. Infusion of intravenous niacin provides a model for acutely improving dietary fat storage, perhaps by suppressing lipolysis in visceral adipose tissue.

Splanchnic spillover of extracellular lipase-generated fatty acids in overweight and obese humans.

OBJECTIVE: Triglyceride-rich lipoproteins, primarily chylomicrons, can contribute to plasma free fatty acid (FFA) concentrations via spillover of fatty acids during intravascular hydrolysis into the venous effluent of some tissues. The present study was undertaken to determine whether spillover occurs in the splanchnic bed of humans. RESEARCH DESIGN AND METHODS: Arterial and hepatic venous blood was sampled in postabsorptive (n = 6; study A) and postprandial (n = 5; study B) obese humans during infusion of carbon-labeled ((14)C or (13)C) oleate and (3)H triolein, the latter incorporated into a lipid emulsion as a surrogate for chylomicrons. Spillover was determined by measuring production of (3)H oleate. RESULTS: Splanchnic spillover was higher than nonsplanchnic systemic spillover in both study A (60 +/- 7 vs. 24 +/- 6%; P < 0.01) and study B (54 +/- 3 vs. 16 +/- 5%; P < 0.005). Because portal vein sampling is not feasible in humans, assumptions regarding actual spillover in nonhepatic splanchnic tissues were required for the spillover calculation. A mathematical model was developed and demonstrated that nonhepatic splanchnic spillover rates in study A and study B of 69 and 80%, respectively, provided the best fit with the data. There was preferential splanchnic uptake of triglyceride fatty acids compared with FFAs in study B (fractional extraction 61 +/- 3 vs. 33 +/- 2%; P < 0.005). CONCLUSIONS: These data confirm previous studies indicating that the transport of FFAs and triglyceride fatty acids are partitioned in tissues and indicate that splanchnic spillover from triglyceride-rich lipoproteins may be a significant source of both portal venous and systemic FFAs.

Triglyceride uptake and lipoprotein lipase-generated fatty acid spillover in the splanchnic bed of dogs.

The action of lipoprotein lipase on triglyceride-rich lipoproteins generates fatty acids that are either transported into tissues or mix with circulating free fatty acids (FFAs) via a process known as spillover. In the present study, arterial, portal vein, and hepatic vein sampling catheters were surgically placed in nine mongrel dogs. The animals were subsequently studied after a 42-h fast during infusion of [14C]oleate and a lipid emulsion containing [3H]triolein; the emulsion was used as a surrogate for the study of chylomicron metabolism. More than one-half of splanchnic [3H]triglyceride uptake occurred in the liver, and substantial fractional spillover of [3H]oleate was observed in both liver and nonhepatic tissues (approximately 50% each). There was a significant correlation between FFA release from nonhepatic tissues (presumably visceral fat) and nonhepatic fractional spillover (R = 0.81, P < 0.01), consistent with a model in which the rate of intracellular lipolysis influences spillover by determining the direction of net fatty acid flow between the cell and the interstitium. There was a significant correlation between "true" and "net" splanchnic spillover (R = 0.84, P < 0.005), the latter representing calculation of spillover between arterial and hepatic venous blood without portal venous data. Metabolism of chylomicron triglycerides in visceral fat may be an important source of portal venous FFAs.

Myocardial uptake of circulating triglycerides in nondiabetic patients with heart disease.

Animal studies indicate that oversupply of fatty acids derived from the action of cardiac lipoprotein lipase (LPL) on plasma lipoproteins may contribute to myocardial dysfunction. However, the contribution of circulating triglycerides to myocardial fatty acid supply in humans is not known. Six postabsorptive nondiabetic subjects who were scheduled for diagnostic coronary angiography were studied. (14)C oleate and a lipid emulsion labeled with (3)H triolein were infused to assess myocardial uptake of free fatty acids (FFAs) and triglycerides, as well as myocardial spillover of LPL-generated fatty acids. Six paired blood samples were taken from the femoral artery and the coronary sinus. Coronary sinus concentrations of unlabeled triglycerides were slightly, but not significantly, lower than arterial (P = 0.12), whereas labeled triglyceride concentrations were significantly lower in the coronary sinus than in the artery (P < 0.05; extraction fraction congruent with 11%). Triglycerides and FFAs accounted for approximately 17% and approximately 83%, respectively, of myocardial fatty acid uptake. Systemic and myocardial fractional spillover of LPL-generated fatty acids was 49.0 +/- 7% and 34.7 +/- 13%, respectively. The myocardium was a minor contributor to systemic triglyceride uptake ( approximately 3%) and a trivial contributor to systemic FFA production ( approximately 0.5%). These results indicate that circulating triglycerides may be a significant source of fatty acids for myocardial respiration.

The use of orlistat in the treatment of obesity, dyslipidaemia and Type 2 diabetes.

Orlistat (tetrahydrolipstatin) is an inhibitor of gastrointestinal lipases, especially pancreatic lipase. It is used as an adjunct to diet and exercise in order to achieve weight loss in obese individuals (body mass index > 30 kg/m2) or in overweight individuals (body mass index > 27 kg/m2) with other risk factors for atherosclerotic vascular disease, such as hypertension, dyslipidaemia or diabetes. Short- and long-term studies of up to 4 years duration have shown the drug to have significant benefits in weight loss, as well as in the reduction in lipids, glucose and haemoglobin A1c, and in time to onset of Type 2 diabetes compared with diet alone or placebo groups. The incremental amount of weight loss that orlistat produces is modest, but sufficient to result in improvement in obesity comorbidities such as elevated blood pressure, dyslipidaemia and hyperglycaemia compared with diet and exercise alone. Orlistat should only be prescribed for individuals who are motivated to adhere to lifestyle modifications, especially dietary fat restriction.