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BackgroundLipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels positively associated with atherosclerotic cardiovascular disease (ASCVD). Lp(a) levels are largely genetically determined. Currently, the only approved therapy for patients with extreme elevations of Lp(a) is lipoprotein apheresis, which eliminates apoB100-containing particles including Lp(a). The current study analyzed the association of free-living diet composition with plasma Lp(a) levels.MethodsDietary composition data from 28 diverse participants was collected via a standardized protocol by registered dietitians using 24-hour recalls. Data were analyzed with the Nutrition Data System for Research (Version 2018). Diet quality was calculated using the Healthy Eating Index (HEI) score. Fasting plasma Lp(a) levels were measured via an isoform-independent ELISA.ResultsSubjects self-reported race/ethnicity [Black (n=18); Hispanic (n=7); White (n=3)]. The mean age was 48.3±12.5 years with 17 males. Median level of Lp(a) was 79.9 nmol/L (34.4-146.0) and was negatively associated with absolute (g/d) and relative (percent calories) intake of dietary saturated fatty acid (SFA) (SFA absolute: R= -0.43, p= 0.02, SFA calorie %: R= -0.38, p= 0.04), absolute palmitic acid intake (palmitic absolute: R= -0.38, p= 0.04), and absolute steric acid intake (steric absolute: R= -0.40, p= 0.03). Analyses of associations with HEI when stratified based on Lp(a) levels > or ≤ 100nmol/L revealed no significant associations with any of the constituent factors.ConclusionsWe found a negative relationship between dietary saturated fatty acid intake and Lp(a) levels in a diverse cohort of individuals. The mechanisms underlying this relationship require further investigation.

Naltrexone/bupropion (NB) is a US Food and Drug Administration-approved antiobesity medication. Clinical trials have shown variable weight loss, with responders and non-responders. NB is believed to act on central dopaminergic pathways to suppress appetite. The Taq1A polymorphism near DRD2 (rs1800497) is associated with the density of striatal dopamine D2 receptors, with individuals carrying the A allele (AA or AG; termed A1+) having 30%-40% fewer dopamine binding sites than those who do not carry the A allele (GG; termed A1-). We performed a pilot study to assess the association of the rs1800497 ANKK1 c.2137G > A (p.Glu713Lys) variant with weight loss with NB treatment in 33 subjects. Mean (SD) weight loss was 5.9% (3.2%) for the A1+ genotype group (n = 15) and 4.2% (4.2%) for the A1- genotype group (n = 18). The mean weight loss for the A1+ genotype group was significantly greater than the predefined clinically significant 4% weight-loss target (one-sample t-test, P = .035), whereas the mean weight loss for the A1- genotype group was not (P = .85). Individuals with the A1+ genotype appear to respond better to NB than A1- individuals.

American adults have gained weight during the COVID-19 pandemic. Little is known about how patients who are medically managed for overweight and obesity, including patients who are prescribed antiobesity pharmacotherapy, have fared.To assess the COVID-19 pandemic's effect on weight, food choices, and health behaviors in patients receiving medical treatment for overweight or obesity.Adult patients treated at an urban academic weight management center between 1 May 2019 and 1 May 2020 were electronically surveyed between 23 February and 23 March 2021. The survey assessed changes in weight, eating, behaviors, and the use of antiobesity medications (AOMs) following issuance of social distancing/stay-at-home policies in March 2020.In 970 respondents, median percent weight change for those taking AOMs was -0.459% [interquartile range -5.46%-(+3.73%)] compared to +2.33% [IQR -1.92%-(+6.52%)] for those not taking AOMs (Medical weight management protected against weight gain during this period of the COVID-19 pandemic. Increased physical activity, decreased alcohol intake, and use of AOMs were factors that contributed to this protective effect.

Lecithin-cholesterol acyltransferase (LCAT) mediates the esterification of free cholesterol (FC) to cholesteryl ester (CE) in HDL and, therefore, plays a critical role in reverse cholesterol transport. MEDI6012, a recombinant human LCAT (rhLCAT) increases HDL-C. Our goal was to interrogate the pathways regulating the increase in HDL-C and effects of rhLCAT on apoB metabolism. Methods: We enrolled five subjects (4 Man, mean age 67) with stable ASCVD into a Phase II, placebo controlled, double-blind, randomized cross-over study to determine the effects of two IV doses of MEDI6012, administered 48-hrs apart, versus placebo, on plasma lipids and lipoproteins. Stable isotope kinetic studies with D2-Leu, 13C-Phe, D2-Glycerol were performed to examine the metabolism of apoB100, ApoA1, ApoA2 and triglyceride. Results: As expected two doses of IV MEDI6012 increased total cholesterol and HDL-C levels significantly (Table1). We did not observe significant changes in other measured lipids or lipoproteins. The significant increase in HDL-C was 34.9±10.3 (p=0.002) and due to an increase in the amount of CE (33±8.9 p=0.001); there was no change in free cholesterol (1.9±1.9). We found no changes in levels of sterols (i.e. Lathosterol) between the two periods. Preliminary in vivo kinetic studies of HDL metabolism in 3 subjects, showed no changes in the mean fractional clearance rate (FCR) or production rate (PR) of apoA1 between placebo (0.3±0.2pool/day, 1.3±0.5 mg/kg/day) and rhLCAT treatment (0.28±0.1pools/day, 1.3±0.3). There were no changes in ApoA2 FCR and PR after rhLCAT administration. Complete data for ApoA1, ApoA2 and ApoB100 and TG kinetics will be presented. Conclusions: In subjects with ASCVD, treatment with rhLCAT increased HDL-C mainly by increasing HDL CE; there were no changes in the FCR or PR of HDL ApoA1 or ApoA2. Together, these results suggest that rhLCAT treatment is associated with increased steady-state transport of CE by HDL.

BACKGROUND Determining the human vitamin E [α-tocopherol (α-T)] requirement is difficult, and novel approaches to assess α-T absorption and trafficking are needed. OBJECTIVE We hypothesized that the dual-isotope technique, using 2 deuterium-labeled [intravenous (IV) d6- and oral d3-] α-T, would be effective in determining α-T fractional absorption. Further, defined liquid meal (DLM) fat or fasting would modulate α-T fractional absorption and lipoprotein transport. METHODS A 3-phase cr ossover design was used. At 0 h, participants received IV d6-α-T and consumed d3-α-T with a 600-kcal DLM (40% or 0% fat) followed by controlled meals or by the 0% fat DLM, a 12-h fast, and then controlled meals. Blood samples and fecal samples were collected at intervals and analyzed by LC-MS. Pharmacokinetic parameters were calculated from plasma tracer concentrations and enrichments. Fractional absorption was calculated from d3- to d6-α-T areas under the curve, from a novel mathematical model, and from the balance method (oral d3-α-T minus fecal d3-α-T excreted). RESULTS Estimated α-T fractional absorption during the 40% fat intervention was 55% ± 3% (mean ± SEM; n = 10), which was 9% less than during the 0% fat intervention (64% ± 3%, n = 10; P

Tissue-type plasminogen activator (tPA) is a major mediator of fibrinolysis and, thereby, prevents excessive coagulation without compromising hemostasis. Studies on tPA regulation have focused on its acute local release by vascular cells in response to injury or other stimuli. However, very little is known about sources, regulation, and fibrinolytic function of noninjury-induced systemic plasma tPA. We explore the role and regulation of hepatocyte-derived tPA as a source of basal plasma tPA activity and as a contributor to fibrinolysis after vascular injury. We show that hepatocyte tPA is downregulated by a pathway in which the corepressor DACH1 represses ATF6, which is an inducer of the tPA gene Plat. Hepatocyte-DACH1–knockout mice show increases in liver Plat, circulating tPA, fibrinolytic activity, bleeding time, and time to thrombosis, which are reversed by silencing hepatocyte Plat. Conversely, hepatocyte-ATF6–knockout mice show decreases in these parameters. The inverse correlation between DACH1 and ATF6/PLAT is conserved in human liver. These findings reveal a regulated pathway in hepatocytes that contributes to basal circulating levels of tPA and to fibrinolysis after vascular injury.

BACKGROUND Completion rates among adolescents who initiate the human papillomavirus (HPV) vaccine 3-dose series are low. SMS text message vaccine reminders are effective, but less is known about the best types for HPV series completion or the ability to assess and target vaccine decision-making stage. OBJECTIVE The aim of this study is to compare the effectiveness of HPV vaccine series completion in minority adolescents who received precision and educational versus conventional SMS text message reminders. METHODS Enrolled parents of adolescents aged 9-17 years who received the first HPV vaccine dose at 1 of the 4 academic-affiliated community health clinics in New York City were randomized 1:1 to 1 of the 2 parallel, unblinded arms: precision SMS text messages (which included stage-targeted educational information, next dose due date, and site-specific walk-in hours) or conventional SMS text messages without educational information. Randomization was stratified according to gender, age, and language. The primary outcome was series completion within 12 months. In post hoc analysis, enrollees were compared with concurrent nonenrollees and historical controls. RESULTS Overall, 956 parents were enrolled in the study. The precision (475 families) and conventional (481 families) SMS text message arms had similarly high series completion rates (344/475, 72.4% vs 364/481, 75.7%). A total of 42 days after the first dose, two-thirds of families, not initially in the preparation stage, moved to preparation or vaccinated stage. Those in either SMS text message arm had significantly higher completion rates than nonenrollees (708/1503, 47.1% vs 679/1503, 45.17%; PP CONCLUSIONS SMS text message reminders led to timely HPV vaccine series completion in a low-income, urban, minority study population and also led to population-wide effects. Educational information did not provide an added benefit to this population. CLINICALTRIAL ClinicalTrials.gov NCT02236273; https://clinicaltrials.gov/ct2/show/NCT02236273

Naltrexone/bupropion (NB) is a US Food and Drug Administration-approved antiobesity medication. Clinical trials have shown variable weight loss, with responders and non-responders. NB is believed to act on central dopaminergic pathways to suppress appetite. The Taq1A polymorphism near DRD2 (rs1800497) is associated with the density of striatal dopamine D2 receptors, with individuals carrying the A allele (AA or AG; termed A1+) having 30%−40% fewer dopamine binding sites than those who do not carry the A allele (GG; termed A1−). We performed a pilot study to assess the association of the rs1800497 ANKK1 c.2137G > A (p.Glu713Lys) variant with weight loss with NB treatment in 33 subjects. Mean (SD) weight loss was 5.9% (3.2%) for the A1+ genotype group (n = 15) and 4.2% (4.2%) for the A1− genotype group (n = 18). The mean weight loss for the A1+ genotype group was significantly greater than the predefined clinically significant 4% weight-loss target (one-sample t-test, P = .035), whereas the mean weight loss for the A1− genotype group was not (P = .85). Individuals with the A1+ genotype appear to respond better to NB than A1- individuals.

We recently reported that acute injection of docosahexaenoic acid (DHA) triglyceride emulsions (tri-DHA) conferred neuroprotection after hypoxic-ischemic (HI) injury in a neonatal mouse stroke model. We showed that exogenous DHA increased concentrations of DHA in brain mitochondria as well as DHA-derived specialized pro-resolving mediator (SPM) levels in the brain. The objective of the present study was to investigate the distribution of emulsion particles and changes in plasma lipid profiles after tri-DHA injection in naïve mice and in animals subjected to HI injury. We also examined whether tri-DHA injection would change DHA- and eicosapentaenoic acid (EPA)-derived SPM levels in the brain. To address this, neonatal (10-day-old) naïve and HI mice were injected with radiolabeled tri-DHA emulsion (0.375 g tri-DHA/kg bw), and blood clearance and tissue distribution were analyzed. Among all the organs assayed, the lowest uptake of emulsion particles was in the brain (

Summary Incomplete understanding of how hepatosteatosis transitions to fibrotic non-alcoholic steatohepatitis (NASH) has limited therapeutic options. Two molecules that are elevated in hepatocytes in human NASH liver are cholesterol, whose mechanistic link to NASH remains incompletely understood, and TAZ, a transcriptional regulator that promotes fibrosis but whose mechanism of increase in NASH is unknown. We now show that increased hepatocyte cholesterol upregulates TAZ and promotes fibrotic NASH. ASTER-B/C-mediated internalization of plasma membrane cholesterol activates soluble adenylyl cyclase (sAC; ADCY10), triggering a calcium-RhoA-mediated pathway that suppresses β-TrCP/proteasome-mediated TAZ degradation. In mice fed with a cholesterol-rich NASH-inducing diet, hepatocyte-specific silencing of ASTER-B/C, sAC, or RhoA decreased TAZ and ameliorated fibrotic NASH. The cholesterol-TAZ pathway is present in primary human hepatocytes, and associations among liver cholesterol, TAZ, and RhoA in human NASH liver are consistent with the pathway. Thus, hepatocyte cholesterol contributes to fibrotic NASH by increasing TAZ, suggesting new targets for therapeutic intervention.

Objective— Apo (apolipoprotein) CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of VLDL (very-low-density lipoprotein) triglyceride (TG) and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are heterozygous for the APOC3 R19X null mutation provided the opportunity to determine the effects of a naturally occurring reduction in apo CIII levels on the metabolism of atherogenic containing lipoproteins. Approach and Results— We conducted stable isotope studies of VLDL-TG and apoB100 in 5 individuals heterozygous for the null mutation APOC3 R19X (CT) and their unaffected (CC) siblings. Fractional clearance rates and production rates of VLDL-TG and apoB100 in VLDL, IDL (intermediate-density lipoprotein), LDL, apo CIII, and apo CII were determined. Affected (CT) individuals had 49% reduction in plasma apo CIII levels compared with CCs ( P P P P Conclusions— These studies demonstrate that 50% reductions in plasma apo CIII, in otherwise healthy subjects, results in a significantly higher rate of conversion of VLDL to LDL, with little effect on direct hepatic uptake of VLDL. When put in the context of studies demonstrating significant protection from cardiovascular events in individuals with loss of function variants in the APOC3 gene, our results provide strong evidence that therapies which increase the efficiency of conversion of VLDL to LDL, thereby reducing remnant concentrations, should reduce the risk of cardiovascular disease.

Supplemental Digital Content is available in the text., Objective— Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. Approach and Results— We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9–108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4–121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. Conclusions— Anacetrapib reduces Lp(a) levels by decreasing its production. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.

BACKGROUND: Factor VIIc, fibrinogen, and plasminogen activator inhibitor 1 (PAI-1) are cardiovascular disease (CVD) risk factors and are modulated, in part, by fat type and amount. OBJECTIVE: We evaluated fat type and amount on the primary outcomes: factor VIIc, fibrinogen, and PAI-1. METHODS: In the Dietary Effects on Lipoproteins and Thrombogenic Activity (DELTA) Trial, 2 controlled crossover feeding studies evaluated substituting carbohydrate or MUFAs for SFAs. Study 1: healthy participants (n = 103) were provided with (8 wk) an average American diet [AAD; designed to provide 37% of energy (%E) as fat, 16% SFA], a Step 1 diet (30%E fat, 9% SFA), and a diet low in SFA (Low-Sat; 26%E fat, 5% SFA). Study 2: participants (n = 85) at risk for CVD and metabolic syndrome (MetSyn) were provided with (7 wk) an AAD, a step 1 diet, and a high-MUFA diet (designed to provide 37%E fat, 8% SFA, 22% MUFA). RESULTS: Study 1: compared with AAD, the Step 1 and Low-Sat diets decreased mean factor VIIc by 1.8% and 2.6% (overall P = 0.0001), increased mean fibrinogen by 1.2% and 2.8% (P = 0.0141), and increased mean square root PAI-1 by 0.0% and 6.0% (P = 0.0037), respectively. Study 2: compared with AAD, the Step 1 and high-MUFA diets decreased mean factor VIIc by 4.1% and 3.2% (overall P

Objective— Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. Approach and Results— Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P P P =0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% ( P P P Conclusions— ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.

Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects.

Inflammation resolution counterbalances excessive inflammation and restores tissue homeostasis after injury. Failure of resolution contributes to the pathology of numerous chronic inflammatory diseases. Resolution is mediated by endogenous specialized proresolving mediators (SPMs), which are derived from long-chain fatty acids by lipoxygenase (LOX) enzymes. 5-LOX plays a critical role in the biosynthesis of two classes of SPMs, lipoxins and resolvins. Cytoplasmic localization of the nonphosphorylated form of 5-LOX is essential for SPM biosynthesis, whereas nuclear localization of phosphorylated 5-LOX promotes proinflammatory leukotriene production. We previously showed that MerTK, an efferocytosis receptor on macrophages, promotes SPM biosynthesis by increasing the abundance of nonphosphorylated, cytoplasmic 5-LOX. Here, we found that activation of MerTK in human macrophages led to ERK-mediated expression of the gene encoding sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), which decreased the cytosolic Ca(2+) concentration and suppressed the activity of calcium/calmodulin-dependent protein kinase II (CaMKII). This in turn reduced the activities of the mitogen-activated protein kinase (MAPK) p38 and the kinase MK2, resulting in the increased abundance of the nonphosphorylated, cytoplasmic form of 5-LOX and enhanced SPM biosynthesis. In a zymosan-induced peritonitis model, an inflammatory setting in which macrophage MerTK activation promotes resolution, inhibition of ERK activation delayed resolution, which was characterized by an increased number of neutrophils and decreased amounts of SPMs in tissue exudates. These findings contribute to our understanding of how MerTK signaling induces 5-LOX-derived SPM biosynthesis and suggest a therapeutic strategy to boost inflammation resolution in settings where defective resolution promotes disease progression.

Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of the HDL-C clearance factors scavenger receptor class B type I (SR-BI) and hepatic lipase and defective selective uptake of HDL cholesteryl ester by the liver. The phenotype could be rescued by re-expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver.

The APOCIII R19X mutation (rs76353203), has been found in ~5% of the Lancaster Old Order Amish. It is a C ->T substitution at the 55th nucleotide in human aolipoprotein C-III mRNA that prevents translation of mature apoC-III protein. The mutation decreases apoC-III levels by ~50% and confers favorable lipid profiles and less coronary artery calcification, providing evidence that ApoC-III deficiency is cardioprotective. This conclusion is supported by recent data in Danish and U.S. cohorts showing a 40% reduction in myocardial infarction rates in people with this mutation. The mechanisms whereby apoc-III deficiency exerts its effects are not fully understood. The aim of this study was to describe the fractional clearance rates (FCR) and production rates (PR) of apoB containing lipoproteins, apoCIII, and very low density lipoprotein (VLDL) tryglyceride (TG) in five Amish sibling pairs (CT vs. CC) discordant for the APOC3 R19X mutation and matched for age and sex. Methods: Sib pairs completed a 24-hr stable isotope kinetic study using leucine and glycerol. Blood samples were collected over 24-hr period. We measured plasma lipids and apoCIII by Elisa. We determined the FCR and PR of VLDL apoB, apoCIII, and VLDL-TG. Results: The CT subjects had a 38% decrease in baseline TG levels compared to CC. ApoCIII levels were reduced by 42% in the CT vs. CC. We observed reductions in VLDL-Chol (49%), IDL-Chol (52%), VLDL-TG(44%), and IDL-TG(39%) in the CT when compared to CC. The changes in plasma levels were due to an increase in the VLDL apoB FCR (p = 0.001) without significant changes in production. VLDL-TG FCR increased by 76% in the CT when compared to CC (p=0.03). We observed no differences in post-heparin plasma levels of hepatic and lipoprotein lipase activity in the CT vs. CC. The plasma changes in apoCIII were due to and increased FCR in the CT compared to CC. Conclusions: Reductions in plasma TG levels in heterozygous apoC-III deficient individuals is due to enhanced FCRs of VLDL-apoB and VLDL-TG.

Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein-cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of insulin’s effect on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of HDL-C clearance factors, scavenger receptor class B type I (SR-BI) and hepatic lipase, and defective selective uptake of HDL-cholesteryl ester by the liver. The phenotype could be rescued by re-expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver.

OBJECTIVE The Action to Control Cardiovascular Risk in Diabetes lipid study (ACCORD Lipid), which compared the effects of simvastatin plus fenofibrate (FENO-S) versus simvastatin plus placebo (PL-S) on cardiovascular disease outcomes, measured only fasting triglyceride (TG) levels. We examined the effects of FENO-S on postprandial (PP) lipid and lipoprotein levels in a subgroup of ACCORD Lipid subjects. RESEARCH DESIGN AND METHODS We studied 139 subjects (mean age of 61 years, 40% female, and 76% Hispanic or black) in ACCORD Lipid, from a total 529 ACCORD Lipid subjects in the Northeast Clinical Network. PP plasma TG, apolipoprotein (apo)B48, and apoCIII were measured over 10 h after an oral fat load. RESULTS The PP TG incremental area under the curve (IAUC) above fasting (median and interquartile range [mg/dL/h]) was 572 (352–907) in the FENO-S group versus 770 (429–1,420) in the PL-S group (P = 0.008). The PP apoB48 IAUC (mean ± SD [μg/mL/h]) was also reduced in the FENO-S versus the PL-S group (23.2 ± 16.3 vs. 35.2 ± 28.6; P = 0.008). Fasting TG levels on the day of study were correlated with PP TG IAUC (r = 0.73 for FENO-S and r = 0.62 for PL-S; each P < 0.001). However, the fibrate effect on PP TG IAUC was a constant percentage across the entire range of fasting TG levels, whereas PP apoB48 IAUC was only reduced when fasting TG levels were increased. CONCLUSIONS FENO-S lowered PP TG similarly in all participants compared with PL-S. However, levels of atherogenic apoB48 particles were reduced only in individuals with increased fasting levels of TG. These results may have implications for interpretation of the overall ACCORD Lipid trial, which suggested benefit from FENO-S only in dyslipidemic individuals.

Background: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date. Methods: Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured. Results: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations. Conclusions: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a). Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01959971.

The mechanisms of HDL-mediated cholesterol transport from peripheral tissues to the liver are incompletely defined. Here the function of scavenger receptor cluster of differentiation 36 (CD36) for HDL uptake by the liver was investigated. CD36 knockout (KO) mice, which were the model, have a 37% increase (P = 0.008) of plasma HDL cholesterol compared with wild-type (WT) littermates. To explore the mechanism of this increase, HDL metabolism was investigated with HDL radiolabeled in the apolipoprotein (125I) and cholesteryl ester (CE, [3H]) moiety. Liver uptake of [3H] and 125I from HDL decreased in CD36 KO mice and the difference, i. e. hepatic selective CE uptake ([3H]125I), declined (–33%, P = 0.0003) in CD36 KO compared with WT mice. Hepatic HDL holo-particle uptake (125I) decreased (–29%, P = 0.0038) in CD36 KO mice. In vitro, uptake of 125I-/[3H]HDL by primary liver cells from WT or CD36 KO mice revealed a diminished HDL uptake in CD36-deficient hepatocytes. Adenovirus-mediated expression of CD36 in cells induced an increase in selective CE uptake from HDL and a stimulation of holo-particle internalization. In conclusion, CD36 plays a role in HDL uptake in mice and by cultured cells. A physiologic function of CD36 in HDL metabolism in vivo is suggested.

Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart-specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36−/−), and double knock-out (hLpL0/Cd36−/−-DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 ± 3.8; hLpL0, 36.2 ± 3.5; Cd36−/−, 57.7 ± 5.5 nmol/g, p 10-fold and reduced HDL by >50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by ∼70% and retinyl ester by ∼50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDL-derived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins.