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Acyl-CoA:cholesterol acyltransferase 2 (ACAT2) generates cholesterol esters (CE) for packaging into newly synthesized lipoproteins and thus is a major determinant of blood cholesterol levels. ACAT2 is expressed exclusively in the small intestine and liver, but the relative contributions of ACAT2 expression in these tissues to systemic cholesterol metabolism is unknown. We investigated whether CE derived from the intestine or liver would differentially affect hepatic and plasma cholesterol homeostasis. We generated liver-specific (ACAT2L−/L−) and intestine-specific (ACAT2SI−/SI−) ACAT2 knockout mice and studied dietary cholesterol-induced hepatic lipid accumulation and hypercholesterolemia. ACAT2SI−/SI− mice, in contrast to ACAT2L−/L− mice, had blunted cholesterol absorption. However, specific deletion of ACAT2 in the intestine generated essentially a phenocopy of the conditional knockout of ACAT2 in the liver, with reduced levels of plasma very low-density lipoprotein and hepatic CE, yet hepatic-free cholesterol does not build up after high cholesterol intake. ACAT2L−/L− and ACAT2SI−/SI− mice were equally protected from diet-induced hepatic CE accumulation and hypercholesterolemia. These results suggest that inhibition of intestinal or hepatic ACAT2 improves atherogenic hyperlipidemia and limits hepatic CE accumulation in mice and that depletion of intestinal ACAT2 is sufficient for most of the beneficial effects on cholesterol metabolism. Inhibitors of ACAT2 targeting either tissue likely would be beneficial for atheroprotection.

Background and Aims: There is some evidence of a cross-sectional, and possibly causal, relationship of lipid levels with leukocyte counts in mice and humans. This study investigates the cross-sectional and longitudinal relationship of blood lipid and lipoprotein levels with leukocyte counts in the UK Biobank cohort., Methods: The primary cross-sectional analysis included 417,132 participants with valid data on lipid measures and leukocyte counts. A subgroup analysis was performed in 333,668 participants with valid data on lipoprotein(a). The longitudinal analysis included 9058 participants with valid baseline and follow-up data on lipid and lipoprotein levels and leukocyte counts. The association of lipid and lipoprotein levels with leukocyte counts was analysed by multivariable linear regression., Results: Several relationships were significant in both cross-sectional and longitudinal analysis. After adjustment for demographic, socioeconomic and other confounding factors, a higher eosinophil count was associated with lower HDL cholesterol and apolipoprotein A-I concentration (p < 0.001). Higher triglycerides levels were associated with higher total leukocyte, basophil, eosinophil, monocyte and neutrophil counts (all p < 0.01). A higher lymphocyte count was associated with a higher apolipoprotein B level (p < 0.001). In the longitudinal analysis, lipoprotein(a) was inversely associated with basophil count in men but not women (p < 0.001)., Conclusions: Triglyceride levels demonstrate a robust positive association with total and differential leukocyte counts suggesting they may be directly involved in leukogenesis. However, unlike in murine models, the remainder of these relationships is modest, which suggests that cholesterol and lipoproteins are minimally involved in leukogenesis in humans., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Caveolin-3 (Cav-3) is an essential scaffolding protein for caveolae formation in cardiomyocytes and targets multiple long QT syndrome (LQTS)-associated ion channels. Mutations in CAV3 have caused an LQT3-like accentuation in late sodium current, I Na (Nav1.5). Here, we characterize a novel CAV3-V37L variant and determine whether it is the substrate for the patient's LQTS., Methods: The proband was a 39-year-old female with drug-induced, sudden cardiac arrest (SCA) with profound QT prolongation (QTc > 600 ms). Genetic testing revealed a rare CAV3-V37L variant of uncertain significance (VUS). Whole-cell patch clamp technique was used to measure I Ks , I Kr , I Na , and I Ca, L currents co-expressed with either CAV3-WT or CAV3-V37L in TSA201 cells and to measure the action potential duration (APD) in control human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) overexpressed with CAV3-WT or CAV3-V37L., Results: CAV3-V37L did not affect Nav1.5 late current. Instead, CAV3-V37L resulted in 1) I Ca, L with slower inactivation, a 1.5 fold increase in peak I Ca, L current density and a 1.1 fold increase in I Ca, L persistent current, 2) dramatically reduced I Ks peak current density by 74.9%, 3) significantly reduced I Kr peak current density by 31.1%, and 4) significantly prolonged the APD in hiPSC-CMs., Conclusions: These functional validation assays enabled the promotion of CAV3-V37L from VUS status to a likely pathogenic variant. Although Nav1.5 was spared, this monogenetic insult precipitated an oligo-proteomic impact with a concomitant gain-of-function of I Ca, L and loss-of-function of both I Ks and I Kr culminating in a marked prolongation of the cardiomyocyte's action potential duration., Competing Interests: Declaration of competing interest MJA is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical. MJA and Mayo Clinic have licensed intellectual property to AliveCor but without remuneration thus far. However, none of these entities have contributed to this study in any manner., (Copyright © 2020. Published by Elsevier B.V.)

Background: Although individual lipid parameters have been frequently examined in association with asymptomatic intracranial arterial stenosis (aICAS), few population-based studies have investigated the lipid profiles associated with aICAS among Chinese adults., Objective: This study aims to characterize the lipid profiles associated with aICAS in rural-dwelling adults in China., Methods: This population-based study included 2027 persons who were aged ≥40 years and free of stroke. Data were collected via interviews, clinical examinations, and laboratory testing. We diagnosed aICAS by integrating transcranial color Doppler with magnetic resonance angiography. Data were analyzed using binary and multinomial logistic regression models., Results: Of the 2027 participants, 154 were detected with aICAS. The multiadjusted odds ratio (95% confidence interval) of aICAS was 1.41 (0.997-2.00) for high small dense low-density lipoprotein cholesterol, 1.44 (1.02-2.04) for high lipoprotein(a), 1.71 (1.21-2.44) for low apolipoprotein A-1, 1.43 (1.00-2.04) for low high-density lipoprotein cholesterol (HDL-C), 1.61 (1.14-2.27) for high apolipoprotein B/apolipoprotein A-1 ratio, 1.95 (1.38-2.76) for high low-density lipoprotein cholesterol/HDL-C ratio, and 1.51 (1.06-2.14) for high total cholesterol/HDL-C ratio. When severity of aICAS was analyzed, high levels of lipoprotein(a), small dense low-density lipoprotein cholesterol, and lipid ratios were significantly associated with an increased likelihood of moderate-to-severe aICAS (P < .05). An increasing number of abnormal lipid measurements was associated with an increased likelihood of aICAS (P for trend <.001)., Conclusion: These findings suggest that lipid profiles for aICAS among rural residents in China are characterized by high atherogenic cholesterol, low antiatherogenic cholesterol, and high ratios of atherogenic-to-antiatherogenic cholesterol or lipoproteins., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We aimed to investigate blood lipid and lipoprotein profiles in patients with dyslipidemia receiving hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) after 8 weeks of omega-3 fatty acid ethyl esters (Omega-3) treatment, using high-performance liquid chromatography with highly-sensitive gel filtration columns., Methods: In this phase 4, randomized, open-label study, patients with dyslipidemia receiving statins were randomized 1:1 to Omega-3 treatment (oral Omega-3 2 g twice daily) or Control (no Omega-3). Primary endpoint was change in mean particle size of low-density lipoprotein (LDL) and small dense LDL (cholesterol monitoring) in the specific 20-lipoprotein fraction assay. Secondary endpoints included changes in lipids, apolipoproteins, and lipoprotein concentrations in fasting blood. Changes were compared between treatments using analysis of covariance, adjusted by baseline fasting triglycerides and age., Results: Fifty-three patients were randomized (Omega-3, n = 24; Control, n = 29). The difference in LDL particle size between Omega-3 and Control groups was significant at week 8 (p = 0.0040). Differences in least squares mean change in concentration from baseline to week 8 between Omega-3 and Control groups were significant for total cholesterol (p = 0.0009), LDL-C (p = 0.0442), non-high-density lipoprotein cholesterol (p = 0.0009), and remnant lipoprotein-cholesterol (p = 0.0396). Differences were significant for apolipoproteins AI, AII, B, B-48, B-100, CII, CIII, and CII/III, but not apolipoprotein E., Conclusions: Significant increases in LDL particle sizes and significant decreases in blood lipid, lipoprotein and apolipoprotein concentrations were observed with Omega-3 compared with Control. Omega-3 may improve blood lipid profile and increase LDL particle size, resulting in an anti-atherogenic profile., (Copyright © 2019. Published by Elsevier B.V.)

Background: Previous studies have demonstrated that elevated cholesterol results in increased white blood cell counts in mouse models. However, there is insufficient evidence to support this in humans., Objective: The objective of the study was to investigate the relationship of plasma lipids with white blood cell counts (basophils, eosinophils, monocytes, neutrophils and lymphocytes) in the Multi-Ethnic Study of Atherosclerosis., Methods: The analysis included 2873 Multi-Ethnic Study of Atherosclerosis participants with a complete white blood count and differential analysis. The cross-sectional association of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels with different white blood cell counts was analyzed by multivariable linear regression., Results: After adjusting for sociodemographic and confounding factors including red blood cell counts, platelet counts, use of lipid-lowering medication, cardiovascular disease risk factors and other lipid measures, and multiple testing correction, a one-standard deviation increment in total cholesterol and low-density lipoprotein cholesterol was associated with 2.8% and 2.3% lower total white blood cell counts, 3.7% and 3.0% lower monocyte counts, and 3.4% and 2.7% lower neutrophil counts (all P < .01). The same increment in logarithm-transformed triglyceride levels was associated with 2.3% higher total white blood cell counts and 4.5% higher lymphocyte counts (both P < .001). Similar results were obtained after excluding participants taking lipid-lowering medication. A one-standard deviation increase in high-density lipoprotein cholesterol was associated with a 1.5% lower white blood cell count (P = .018) but was not significantly associated with changes in any individual cell type., Conclusion: While significant associations were observed between plasma lipid levels and white blood cell populations, the heterogeneous and modest nature of these relationships makes it hard to support the hypothesis that lipids are in the causal pathway for leukogenesis in humans., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)