Effect of Fenofibrate and Niacin on Intrahepatic Triglyceride Content, Very Low-Density Lipoprotein Kinetics, and Insulin Action in Obese Subjects with Nonalcoholic Fatty Liver Disease

Abstract

Context: Nonalcoholic fatty liver disease is associated with risk factors for cardiovascular disease, particularly increased plasma triglyceride (TG) concentrations and insulin resistance. Fenofibrate and extended release nicotinic acid (Niaspan) are used to treat hypertriglyceridemia and can affect fatty acid oxidation and plasma free fatty acid concentrations, which influence intrahepatic triglyceride (IHTG) content and metabolic function.

Objective: The objective of the study was to determine the effects of fenofibrate and nicotinic acid therapy on IHTG content and cardiovascular risk factors.

Experimental Design and Main Outcome Measures: We conducted a randomized, controlled trial to determine the effects of fenofibrate (8 wk, 200 mg/d), Niaspan (16 wk, 2000 mg/d), or placebo (8 wk) on IHTG content, very low-density lipoprotein (VLDL) kinetics, and insulin sensitivity.

Setting and Participants: Twenty-seven obese subjects with nonalcoholic fatty liver disease (body mass index 36 ± 1 kg/m², IHTG 23 ± 2%) were studied at Washington University.

Results: Neither fenofibrate nor Niaspan affected IHTG content, but both decreased plasma TG, VLDL-TG, and VLDL-apolipoprotein B concentrations (P < 0.05). Fenofibrate increased VLDL-TG clearance from plasma (33 to 54 ml/min; P < 0.05) but not VLDL-TG secretion. Niaspan decreased VLDL-TG secretion (27 to 15 μmol/min; P < 0.05) without affecting clearance. Both fenofibrate and Niaspan decreased VLDL-apolipoprotein B secretion (1.6 to 1.2 and 1.3 to 0.9 nmol/min, respectively; P < 0.05). Niaspan reduced hepatic, adipose tissue, and muscle insulin sensitivity (P < 0.05), whereas fenofibrate had no effect on insulin action.

Conclusions: Fenofibrate and Niaspan decrease plasma VLDL-TG concentration without altering IHTG content. However, the mechanism responsible for the change in VLDL-TG concentration is different for each drug; fenofibrate increases plasma VLDL-TG clearance, whereas nicotinic acid decreases VLDL-TG secretion.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver abnormalities characterized by an excessive accumulation of intrahepatic triglyceride (IHTG). It has recently become clear that NAFLD is associated with metabolic abnormalities that are important risk factors for cardiovascular disease (CVD), including insulin resistance, increased serum triglyceride (TG) concentration, and the metabolic syndrome (1, 2). Therefore, it is not surprising that subjects with NAFLD are at increased risk of developing CVD events (3). In addition, NAFLD is associated with an increased risk of CVD, independent of metabolic risk factors (4, 5).

The mechanisms responsible for excessive IHTG must involve an imbalance between factors that regulate hepatic TG production [uptake of free fatty acid (FFA) from plasma and incorporation into very low density lipoproteins (VLDL) and de novo lipogenesis] and factors that regulate hepatic TG disposal [fatty acid oxidation (FAO) and TG export in VLDL]. Two common classes of pharmacological agents used to treat hypertriglyceridemia to prevent CVD events, namely fibrates and nicotinic acid derivatives, act by altering metabolic processes that could affect hepatic TG metabolism and IHTG content. Fibrates stimulate peroxisome proliferator-activated receptor (PPAR)-α, which regulates the expression of genes involved in mitochondrial FAO (6). Data from studies conducted in animal models demonstrate that fibrate therapy increases hepatic FAO and resolves steatosis (7, 8). Nicotinic acid therapy transiently inhibits lipolysis of adipose tissue TG, resulting in a decrease in FFA release into the bloodstream, which could decrease hepatic VLDL-TG secretion (9, 10).

The purpose of the present study was to determine whether pharmacological manipulation of fatty acid metabolism with either fenofibrate (Lofibra; Teva Pharmaceuticals, North Wales, PA) or an extended-release (ER) niacin (Niaspan; Abbott Laboratories, Abbott Park, IL) alters IHTG content, FFA kinetics, VLDL-TG and VLDL-apolipoprotein B-100 (apoB) metabolism, and multiorgan insulin sensitivity in obese insulin-resistant subjects with NAFLD. We conducted a randomized, placebo-controlled trial to test the hypothesis that both fenofibrate and ER niacin would reduce IHTG content and decrease plasma VLDL-TG concentration by effects on FFA and VLDL metabolism. Stable isotope tracer infusions and the euglycemic-hyperinsulinemic clamp procedure were used to evaluate insulin sensitivity and VLDL kinetics.

Subjects and Methods

Subjects

Twenty-seven obese subjects with NAFLD [18 women and nine men; age 42 ± 2 yr, body mass index (BMI) 36 ± 1 kg/m², IHTG 23 ± 2% (range 6.6–43.2%)] participated in this study (Table 1). All subjects completed a comprehensive medical evaluation, which included a 2-h oral glucose tolerance test and magnetic resonance spectroscopy. Potential participants who were not obese (BMI ≥30 kg/m²) or did not have NAFLD (IHTG content ≥5.6%) were excluded. In addition, those who smoked cigarettes, consumed 20 g/d or more of alcohol, had severe hypertriglyceridemia (>3.4 mmol/liter), or had diabetes were excluded. The potential presence of chronic liver disease was evaluated by a careful medical history. Blood testing for either anti-hepatitis C virus or anti-hepatitis B core antigen was not performed as part of the study protocol. However, most of the subjects who had abnormal liver biochemistries had been tested for viral hepatitis before enrollment and had nonreactive HB antigen and anti-HCV. All subjects were weight stable (≤2% change in weight) and sedentary (exercise <1 h/wk) for at least 3 months before enrollment and throughout the entire duration of the study. Subjects provided their written informed consent before participating in this study, which was approved by the Human Research Protection Office of Washington University School of Medicine.

Experimental Design

Body composition

Total body fat and fat-free mass (FFM) were determined by using dual-energy x-ray absorptiometry (Delphi-W densitometer; Hologic, Waltham, MA), intraabdominal and sc abdominal adipose tissue volumes were quantified by using magnetic resonance imaging (Siemens, Iselin, NJ), and IHTG content was measured by using magnetic resonance spectroscopy (1.5T Siemens Magneton Vision scanner; Siemens, Erlanger, Germany), as previously described (11, 12).

Hyperinsulinemic-euglycemic clamp procedure

Subjects were admitted to the Clinical Research Unit (CRU) in the evening before the study and consumed a standard meal (∼12 kcal/kg FFM) at 1900 h and a 250-kcal liquid snack (Ensure; Ross Laboratories, Columbus, OH) at 2000 h. At 0600 h the following morning, a two-stage, 9.5-h hyperinsulinemic-euglycemic clamp procedure was performed, as previously described (11). [6,6-²H₂]glucose and [2,2-²H₂]palmitate were infused to assess glucose and fatty acid kinetics, and 20% dextrose enriched to 2.5% with [6,6-²H₂]glucose was infused to maintain euglycemia (∼5.5 mmol/liter). Insulin was infused at a rate of 20 mU/m² body surface area per minute during stage 1 (3.5–6.5 h) to evaluate adipose tissue and hepatic insulin sensitivity and at a rate of 50 mU/m² body surface area per minute during stage 2 (6.5–9.5 h) to evaluate skeletal muscle insulin sensitivity (11). Blood samples were obtained immediately before starting the tracer infusion and every 10 min during the final 30 min of the basal period and stages 1 and 2 of the clamp procedure.

VLDL kinetics study

Approximately 1 wk after the clamp procedure was performed, subjects were readmitted to the CRU, at which time they consumed the same evening meal and snack as in the evening before the clamp procedure. At 0600 h the following morning, VLDL kinetics were determined as previously described (12). A bolus of [1,1,2,3,3-²H₅]glycerol (75 μmol/kg) was administered, and an infusion of [5,5,5-²H₃]leucine (0.12 μmol/kg per minute; priming dose 7.2 μmol/kg) was started and maintained for 12 h. Blood samples were obtained immediately before starting the tracer infusion and at 5, 15, 30, 60, 90, and 120 min and then every hour for 10 h. Aliquots of plasma were kept in the refrigerator to isolate VLDL, and the remaining plasma samples were stored at −80 C until additional analyses were performed.

Intervention

After baseline studies were completed, subjects were randomly assigned in a double-blind fashion to one of three treatment groups: 1) 8 wk treatment with placebo, 2) 8 wk treatment with fenofibrate 200 mg/d, or 3) 16 wk treatment with ER niacin (Niaspan) (titrated from 500 mg/wk to final dose of 2000 mg/wk during the first 3 wk) (kindly provided by Abbott Laboratories). The duration of Niaspan therapy was greater than fenofibrate because of the time needed to titrate Niaspan to its full dose and because data from several studies suggest that niacin-induced insulin resistance (increase in plasma glucose and insulin concentrations) dissipates by 16 wk of therapy (13–17). Subjects had contact with our research nurse every week; they were seen in the outpatient CRU every 2 wk and were contacted by phone every 2 wk to review any potential problems, enhance compliance with treatment, and ensure they were weight stable and did not increase their physical activity. In addition, compliance with therapy was monitored by pill count during bimonthly visits.

Postintervention studies

Body composition measurements and metabolic studies performed before treatment were repeated at the end of treatment. The last placebo or drug dose was given in the evening before the second metabolic study.

Sample analyses

VLDL isolation and recovery from plasma

Plasma VLDL was prepared as previously described (18). Approximately 1.5 ml plasma were transferred into OptiSeal polyallomer tubes (Beckman Instruments, Palo Alto, CA), overlaid with a NaCl/EDTA solution (1.006 g/ml), and centrifuged at 100,000 × g for 16 h at 10 C in an Optima LE-80K preparative ultracentrifuge equipped with a type 50.4 Ti rotor (Beckman Instruments). The top layer containing VLDL was removed by tube slicing (CentriTube slicer; Beckman Instruments). ApoB-100 concentration was measured immediately in a fresh aliquot of the VLDL fraction and in plasma; the remaining samples were stored at −80 C until final analyses were performed. In routinely performed quality control experiments in our laboratory, we found that TG recovery is greater than 95% when adding the concentrations of TG in the VLDL fraction (d<1.006 g/liter; top of the tube) and non-VLDL fraction (d>1.006 g/ml; bottom of the tube after VLDL recovery) and comparing this value to the TG concentration measured in whole plasma. In addition, we measured VLDL-apoB-100 concentration by using an immunoturbidimetric assay after ultracentrifugation and compared it with the VLDL particle concentration assessed by subjecting whole plasma of the same subjects to proton nuclear magnetic resonance spectroscopy; the results from these two procedures were in excellent agreement (58 ± 3 nmol VLDL-apoB-100 per liter plasma vs. 54 ± 2 nmol VLDL particles per liter plasma, respectively).

Substrate concentrations and tracer to tracee ratios (TTRs)

The plasma concentration of glucose was determined by using an automated glucose analyzer; insulin was determined by RIA (Linco Research, St. Louis, MO); total cholesterol and high-density lipoprotein cholesterol were determined by using commercially available assays; FFA was determined by gas chromatography (19); total plasma TG and VLDL-TG were determined by using a colorimetric enzymatic kit (Sigma Chemicals, St. Louis, MO); total plasma apoB and VLDL-apoB were determined by using a turbidimetric immunoassay (Wako Pure Chemical Industries, Osaka, Japan); and β-hydroxybutyrate (BHB) was determined by using a colorimetric assay (BioVision Inc., Mountain View, CA). Plasma glucose, palmitate, and leucine TTRs, glycerol TTR in VLDL-TG, and leucine TTR in VLDL-apoB were determined by using gas chromatography-mass spectrometry (12).

Calculations

The homeostasis model assessment of insulin resistance (HOMA-IR) was determined from fasting plasma glucose and insulin concentrations (20). Substrate (glucose and palmitate) rate of appearance (Ra) in plasma was calculated by dividing the substrate tracer infusion rate by the average plasma substrate TTR during the last 30 min of the basal period and stages 1 and 2 of the clamp procedure. During the clamp, endogenous glucose production rate was calculated by subtracting the glucose infusion rate (i.e. enriched dextrose solution) from total glucose Ra; glucose rate of disappearance (Rd) was assumed to be equal to total glucose Ra (i.e. the sum of endogenous glucose Ra and the rate of infused glucose).

Total FFA Ra was calculated by dividing palmitate Ra by the proportional contribution of palmitate to total plasma FFA concentration. The suppression of glucose Ra and FFA Ra during stage 1 of the clamp procedure were used as a measure of hepatic and adipose tissue insulin sensitivity, respectively, and the stimulation of glucose Rd during stage 2 of the clamp procedure was used as a measure of skeletal muscle insulin sensitivity (11).

Hepatic secretion rates of VLDL-TG and VLDL-apoB were calculated by multiplying plasma VLDL-TG or VLDL-apoB concentration by VLDL-TG or VLDL-apoB fractional turnover rate, determined by fitting the TTR data to a compartmental model (12). Plasma VLDL-TG clearance rate was calculated as VLDL-TG Rd divided by VLDL-TG concentration (12).

Statistical analysis

A one-way ANOVA was used to evaluate differences between groups at baseline. The effect of treatment was determined by using repeated-measures ANOVA, with time as within-subject factor (before vs. after treatment) and group as between-subject factor (placebo vs. fenofibrate vs. niacin). When significant interactions between time and group were found, a Student’s t test for paired samples was used to evaluate the effect of treatment. Results are presented as means ± sem. P < 0.05 was considered statistically significant.

Results

Body composition

No significant differences in age, sex, and baseline body composition were detected among the three groups (Table 1). Neither fenofibrate nor niacin treatment changed body weight, body fat content, or fat distribution.

Substrate concentrations

Baseline metabolic variables did not differ among the three treatment groups (Table 2). Treatment with niacin, but not fenofibrate, increased mean basal plasma insulin (P = 0.01) and glucose (P = 0.04) concentrations, and HOMA-IR (P = 0.009) (Table 2). Treatment with either niacin or fenofibrate decreased plasma TG, VLDL-TG, and VLDL-apoB concentrations; both treatments also caused a similar decrease in total plasma apoB concentrations, but the decrease obtained with niacin therapy did not reach statistical significance (P = 0.085). Plasma FFA concentration did not change significantly with either niacin or fenofibrate treatment, but niacin increased, whereas fenofibrate decreased, plasma BHB concentrations.

Substrate kinetics and insulin sensitivity

Baseline substrate kinetics were not different among the three groups of subjects (Fig. 1). Basal FFA Ra did not change with either niacin or fenofibrate therapy (Fig. 1A), whereas basal glucose Ra increased after niacin (P = 0.036) but not fenofibrate therapy (Fig. 1B).

The ability of insulin to suppress glucose Ra (an index of hepatic insulin sensitivity) and FFA Ra (an index of adipose tissue insulin sensitivity) during stage 1 and to stimulate glucose Rd (an index of skeletal muscle insulin sensitivity) during stage 2 of the clamp procedure were not different among the three groups of subjects at baseline (Table 3). Fenofibrate treatment did not affect insulin sensitivity, whereas treatment with niacin reduced insulin-mediated stimulation of glucose Rd, suppression of glucose Ra, and suppression of FFA Ra (Table 3).

VLDL-TG and VLDL-apoB kinetics

Treatment with either fenofibrate or niacin reduced VLDL-TG and VLDL-apoB concentrations (Table 2) by affecting different metabolic pathways. Fenofibrate therapy increased VLDL-TG clearance from plasma (P = 0.017) but did not affect the hepatic VLDL-TG secretion rate (P = 0.692) (Fig. 2, A and B). Niacin therapy decreased VLDL-TG secretion rate (P = 0.019) but did not affect plasma VLDL-TG clearance (P = 0.976) (Fig. 2, A and B). Both fenofibrate and niacin decreased the secretion rate (P = 0.006 and 0.016, respectively) of VLDL-apoB (Fig. 2C). Fenofibrate increased the molar ratio of VLDL-TG to VLDL-apoB secretion rates (P = 0.038,) whereas niacin did not affect the relationship in secretion rates (P = 0.750) (Fig. 2D).

Discussion

NAFLD is associated with multiorgan insulin resistance (11), alterations in VLDL-TG kinetics (12), increased serum TG (21, 22), and CVD (1, 4, 5). We conducted a randomized, placebo-controlled trial to evaluate the effect of two classes of pharmacological agents used to treat hypertriglyceridemia on IHTG content, insulin sensitivity, and VLDL kinetics in obese subjects with NAFLD. These agents were chosen because of their potential effects on intrahepatic FAO (fenofibrate) and release of FFA into plasma and hepatic fatty acid uptake (niacin), which could affect IHTG content and hepatic metabolic function. Although IHTG content was not affected by either treatment, both fenofibrate and niacin reduced plasma TG concentrations by altering VLDL-TG metabolism. However, the mechanisms responsible for this effect differed between the two agents; fenofibrate increased VLDL-TG clearance from plasma, whereas niacin decreased VLDL-TG secretion rate. Even though both treatments improved the dyslipidemia associated with NAFLD, neither improved insulin action; fenofibrate therapy did not affect insulin sensitivity, and niacin therapy caused a decline in hepatic, skeletal muscle, and adipose tissue insulin sensitivity.

We hypothesized that fenofibrate therapy would reduce IHTG by increasing intrahepatic FAO because fibrates activate PPAR-α, which regulates the expression of genes involved in FAO (7), and activating PPAR-α decreases liver TG content in obese (23) and insulin-resistant rodent models (24). However, fenofibrate therapy did not affect IHTG content in our subjects, even though we specifically selected those who had considerable steatosis (∼25% liver volume as IHTG) in an effort to maximize our ability to detect a reduction in IHTG. The differences between our results and those reported in rodents could be due to species-related differences in PPAR-α activity. PPAR-α expression and DNA binding activity in human hepatocytes are more than 10-fold lower than those observed in mice (25, 26). Moreover, certain PPAR response elements, such as the acyl CoA oxidase gene, do not respond to PPAR ligands in humans as they do in rodent models (27). In fact, we found that fenofibrate therapy decreased plasma BHB concentrations, which has been considered a surrogate marker of hepatic FAO (28). Therefore, our findings suggest that fenofibrate therapy does not increase intrahepatic FAO enough to reduce IHTG content. Two previous open-label trials that evaluated the effect of fenofibrate therapy on IHTG content in human subjects reported contradictory results; in one study conducted in elderly subjects, IHTG content, assessed by magnetic resonance spectroscopy, did not change after fenofibrate therapy (29), whereas in the other study conducted in patients with metabolic syndrome, fenofibrate therapy was associated with resolution of ultrasonographic evidence of steatosis in almost half of the subjects (30). The reason for the differences between studies is not clear but could be related to differences in patient populations or techniques used to assess IHTG. It is unlikely that the duration of treatment in our study (8 wk) was too short to affect IHTG content because IHTG can change rapidly and decreases after only 48 h of calorie restriction (31).

We also hypothesized that Niaspan, an ER formulation of nicotinic acid (32), would decrease IHTG content by decreasing adipose tissue lipolytic activity and thereby decrease FFA delivery to the liver. Although crystalline (immediate release) nicotinic acid has been shown to rapidly inhibit lipolysis and lower plasma FFA concentration, this effect is followed by a large rebound in lipolytic rate and increase in plasma FFA concentration within 1 h (33). In contrast, Niaspan decreases lipolytic rate and plasma FFA concentration for hours but causes a small increase in lipolytic activity 9 h later (16). Therefore, Niaspan causes less of a rebound in lipolytic rate than that observed with crystalline nicotinic acid, but the rebound is not completely abolished. In our subjects, 16 wk of Niaspan therapy did not affect adipose tissue lipolytic rate, plasma FFA concentrations, or IHTG content. Therefore, we were unable to test the hypothesis that adipose tissue lipolytic activity and plasma FFA availability are involved in the pathogenesis of NAFLD.

Niacin therapy decreased plasma TG concentration by decreasing VLDL-TG secretion rate, even though it did not affect adipose tissue lipolytic rate or the availability of plasma FFA for hepatic TG synthesis. These results are consistent with the findings from other studies that evaluated the effect of the immediate-release nicotinic acid on VLDL-TG kinetics in other patient populations (10, 34). Niacin directly inhibits the activity of diacylglycerol acyltransferase 2, which catalyzes the final reaction in triglyceride synthesis (35), and accelerates hepatocellular degradation of apoB with a decrease in apoB secretion (36). In addition, we found Niaspan therapy was associated with an increase in plasma BHB concentration, suggesting that Niaspan increased intrahepatic FAO, which could reduce the availability of fatty acids for TG synthesis. Therefore, the results obtained in vivo from the present study, in conjunction with results obtained from cell culture systems, suggest that Niaspan’s putative intrahepatic effects influence VLDL-TG metabolism.

Although fibrate therapy can induce a marked reduction in plasma VLDL-TG concentration, the mechanisms responsible for this effect are not fully understood and differ among fibrate compounds. Gemfibrozil reduces VLDL-TG concentration by decreasing hepatic secretion and increasing peripheral clearance of both VLDL-TG and apoB (37, 38), whereas bezafibrate increases clearance and decreases production rate of apoB (39, 40). In contrast, clofibrate reduces VLDL-TG concentration by increasing VLDL-TG clearance, without affecting secretion rate (38). The data from the present study demonstrate that fenofibrate also reduces VLDL-TG concentration by increasing VLDL-TG clearance, as shown in previous studies (41, 42), without affecting secretion rate. In addition, we found that fenofibrate therapy decreased VLDL-apoB secretion, despite an unchanged rate of VLDL-TG secretion, suggesting the production of TG-rich nascent VLDL particles. Therefore, it is likely that the large size of newly secreted VLDL particles, which can be delipidated and cleared faster than smaller particles, in conjunction with the known effect of fibrate in stimulating lipoprotein lipase activity (43, 44), contributed to the increased rate of VLDL-TG clearance observed in our study subjects.

Both fenofibrate and Niaspan therapy decreased VLDL-apoB secretion rate, demonstrating both drugs decreased the number of VLDL particles secreted by the liver. The decrease in secreted apoB-containing lipoproteins was associated with a decline in VLDL-apoB concentration, and with a reduction in plasma total apoB concentration, although the decrease achieved with niacin was not statistically significant. Although we did not measure LDL-apoB concentrations directly, the decrease in total apoB was likely due to a decrease in the number of LDL particles because LDL is the major source of plasma apoB.

Crystalline (immediate release) nicotinic acid often decreases insulin sensitivity and increases plasma glucose concentration (13, 45–50). The alteration in insulin action has been attributed to the rebound in adipose tissue FFA release and increase in plasma FFA concentrations (48, 50, 51). We found that 16 wk of high-dose ER niacin therapy caused multiorgan impairment in insulin action in obese subjects with NAFLD. Although treatment with ER niacin caused adipose tissue insulin resistance (impaired insulin mediated suppression of adipose tissue lipolytic rate), we did not observe an increase in the basal rate of FFA release into plasma or plasma FFA concentration, presumably because the increase in basal plasma insulin concentrations that occurred after ER niacin treatment prevented an increase in basal lipolytic activity. Therefore, our data suggest that niacin’s deleterious effect on insulin action is unrelated to FFA kinetics.

Our study has several strengths and limitations. The strengths of the present study include: 1) the randomized controlled design; 2) the careful selection of study subjects to maximize our ability to detect treatment effects because subjects were obese with high IHTG content, had moderate and responsive hypertriglyceridemia, and did not have the confounding effect of diabetes or diabetes therapy; and 3) simultaneous evaluation of drug intervention on both VLDL metabolism and multiorgan insulin sensitivity, which provided a comprehensive assessment of the metabolic effects of therapy. A potential limitation of our study is the small sample size. However, the sensitivity and reproducibility of our main outcome measures allowed us to detect statistically significant metabolic effects of therapy and rule out clinically or physiologically important effects on IHTG content. A second limitation is that our study was not designed to determine the molecular mechanisms responsible for the effects of fenofibrate and niacin on VLDL metabolism and insulin sensitivity. Additional studies are needed to identify the cellular processes responsible for our in vivo observations.

In conclusion, fenofibrate and niacin therapy decrease plasma TG concentration in obese subjects with NAFLD, without affecting IHTG content. The mechanism responsible for the decrease in circulating TG differs between the two agents: fenofibrate increases VLDL-TG clearance from plasma, whereas niacin decreases VLDL-TG secretion. Niacin therapy decreases insulin sensitivity in the liver, skeletal muscle, and adipose tissue. However, the mechanism responsible for this adverse effect on insulin action is not known and requires further study.

Acknowledgments

The authors thank Adewole Okunade, Freida Custodio, and Jennifer Shew for technical assistance; the staff of the Clinical Research Unit for their help in performing the studies; and the study subjects for their participation. Niaspan capsules were provided by Abbott Laboratories (Abbott Park, IL).

This study was supported by National Institutes of Health Grants DK 37948, DK 56341 (to Clinical Nutrition Research Unit), RR024992 (to Clinical and Translational Science Award), and RR-00954 (to Biomedical Mass Spectrometry Resource).

Disclosure Summary: The authors have nothing to declare.

Abbreviations

 
• apoB

  Apolipoprotein B

 
• BHB

  β-hydroxybutyrate

 
• BMI

  body mass index

 
• CRU

  Clinical Research Unit

 
• CVD

  cardiovascular disease

 
• ER

  extended-release

 
• FAO

  fatty acid oxidation

 
• FFA

  free fatty acid

 
• FFM

  fat-free mass

 
• HOMA-IR

  homeostasis model assessment of insulin resistance

 
• IHTG

  intrahepatic triglyceride

 
• NAFLD

  nonalcoholic fatty liver disease

 
• PPAR

  peroxisome proliferator-activated receptor

 
• Ra

  rate of appearance

 
• Rd

  rate of disappearance

 
• TG

  triglyceride

 
• TTR

  tracer to tracee ratio

 
• VLDL

  very low-density lipoprotein