Baseline Insulin Resistance Is a Determinant of the Small, Dense Low-Density Lipoprotein Response to Diets Differing in Saturated Fat, Protein, and Carbohydrate Contents

Individual responses to diet vary but causes other than genetics are poorly understood. This study sought to determine whether baseline values of homeostasis model assessment (HOMA-IR) was related to changes in small, dense low-density lipoprotein (sdLDL, i.e., LDL4, d = 1.044–1.063 g/mL) amounts quantified by isopycnic density profiling, in mildly hypercholesterolemic subjects (n = 27) consuming one of three low saturated fatty acid (SFA) diets: Dietary Approaches to Stop Hypertension (DASH), Beef in an Optimal Lean Diet (BOLD) and BOLD plus extra protein (BOLD+) when compared to a higher-SFA healthy American diet (HAD). The diets were consumed in random order for 5 wk, with 1 wk between diets. BOLD+ reduced fractional abundance (%) LDL4 (p < 0.05) relative to HAD, DASH and BOLD, and reductions in % LDL4 correlated with reductions in triglycerides (p = 0.044), total cholesterol (p = 0.014), LDL cholesterol (p = 0.004) and apolipoprotein B (p < 0.001). Responses to the four diets were similar (~12% decrease in % LDL4, p = 0.890) in the lower (<2.73 median) HOMA-IR subgroup but differed across diet conditions in the higher HOMA-IR subgroup (p = 0.013), in which % LDL4 was reduced with BOLD+ (−11%), was unchanged in BOLD and increased with the HAD (8%) and DASH (6%) diets (p < 0.05 for BOLD+ vs. HAD). Individual responses to diet interventions are influenced by presence and degree of insulin resistance as measured by HOMA-IR.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Not Induced in Artificial Human Inflammation and Is Not Correlated with Inflammatory Response

ABSTRACT Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response. However, knowledge about the role and kinetics of PCSK9 in human inflammation is currently insufficient. This study aimed to investigate the interaction between inflammation and lipid metabolism, including the possible role of PCSK9. A single-blinded, placebo-controlled cross-over study using the human endotoxin model was performed. Ten healthy men received lipopolysaccharide (LPS) or placebo on two different study days after overnight fasting. Lipoproteins as well as PCSK9 were measured repetitively over 48 h. PCSK9 plasma concentrations were not induced by LPS infusion, and no correlation between PCSK9 plasma concentrations and the degree of inflammation could be identified. The observed low-density lipoprotein (LDL) response to inflammation was more complex than anticipated, especially in the very early phase after the inflammatory stimulus. Baseline concentrations of LDL, as well as high-density lipoprotein (HDL), correlated negatively with inflammatory response. Our data suggest that the lipoprotein response to inflammation is independent of PCSK9. The proposed elevations of PCSK9 and suspected correlations between PCSK9 levels and inflammatory response are not supported by our data. (This study has been registered at ClinicalTrials.gov under registration no. NCT03392701.)

Biological Response to Meal Ingestion: Gender Differences

In a previous study, we demonstrated that women enjoyed and tolerated lower meal loads than men. Hence, we hypothesized that with the same meal load, their postprandial response is more pronounced than in men. We performed a randomized parallel trial in 12 women and 12 men comparing the postprandial responses to a palatable comfort meal. We measured homeostatic sensations (hunger/satiety, fullness) and hedonic sensations (digestive well-being, mood) on 10 cm scales, vagal tone by heart ratio variability and the metabolomic profile before and after meal ingestion. Gender differences were analyzed by repeated measures ANCOVA. Overall (n = 24), ingestion of the probe meal induced satiation, fullness, digestive well-being and improved mood (main time-effect p ≤ 0.005 for all). Women exhibited a more intense sensory experience, specially more postprandial fullness, than men [main gender-effect F (1, 21) = 7.14; p = 0.014]; hedonic responses in women also tended to be stronger than in men. Women exhibited more pronounced effects on vagal tone [main gender-effect F (1, 21) = 5.5; p = 0.029] and a different lipoprotein response than men. In conclusion, our data indicate that gender influences the responses to meal ingestion, and these differences may explain the predisposition and higher incidence in women of meal-related functional disorders.

Abstract 394: Ldl-cholesterol, ApoB100 Kinetics and Atherosclerosis in Ldlr-deficient Yucatan Minipigs: A New Model for Familial Hypercholesterolemia

Lack of animal models with human-like lipoprotein metabolism and pathology has hampered translational research in atherosclerosis. Recently, a model of familial hypercholesterolemia was developed in Yucatan miniature pigs, in which the LDL receptor (LDLR) was deleted through gene targeting of exon 4. The objective of the present study was to determine the plasma lipoprotein response to a high fat diet and the kinetics of apolipoprotein (apo) B metabolism in LDLR-deficient miniature pigs. LDLR+/+ (n=5), LDLR+/- pigs (n=6) and LDLR-/- pigs (n=5) were fed a diet containing 34% kcal from fat and 0.2% cholesterol (C). At 6 weeks, the kinetics of plasma apoB100 (fasting) were measured using stable isotopic techniques and multi-compartmental modeling. In chow-fed pigs, LDL-C was 0.8mM, 1.3mM and 14mM in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. On diet for 6 weeks, LDL-C increased 1.3-fold (to 1.09mM), 1.7-fold (to 2.3mM) and 1.2-fold (to 15.8mM) in LDLR+/+, LDLR+/- and LDLR-/- pigs, respectively. The effect of genotype or diet on plasma TG and HDL-C was modest. Compared to LDLR+/+ pigs, VLDL apoB100 pool sizes increased 1.4-fold in LDLR+/- and 1.7-fold in LDLR-/- pigs, due primarily to a decrease in fractional catabolic rates (FCR) of 18% and 63%, respectively. Compared to LDL+/+ pigs, LDL apoB100 pool sizes increased 2.2-fold and 14-fold in LDLR+/- and LDLR-/-, respectively, which was due to both 1.5-fold and 2-fold increases in production rates and 24% and 85% decreases in FCR, respectively. At 23 weeks, raised lesion area in the abdominal aorta was 3.3% in LDLR+/- pigs and 48.5% in LDLR-/- pigs. In the left anterior descending coronary artery, lesion area was 14.7x10 3 μm 2 in LDLR+/- pigs and 656x10 3 μm 2 in LDLR-/- pigs. This model should prove useful for translational research in lipoprotein metabolism and atherosclerosis.