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Lipids are carried in plasma by lipoproteins, which have an external hydrophilic region containing proteins, phospholipids, and nonsterified cholesterol, and an internal hydrophobic core, containing triacylglycerols (TAGs) and cholesterol esters. Based on their density, different lipoprotein groups can be distinguished in blood. (1) Chylomicrons, which contain mainly TAGs synthesized in the intestinal mucosa from fatty acids (FAs) and monoacylglycerols from the diet. A lipoprotein lipase (LpL) in capillary endothelial cells hydrolyze TAG. The freed FA enter the cells, where they are oxidized (muscle) or stored (adipose tissue). The chylomicron remnants, reduced to its protein component (apolipoprotein B-48, or apo-48) bind to liver receptors and are internalized and cleared from circulation. (2) Very low density lipoproteins (VLDLs) are synthesized in hepatocytes. They are rich in TAG and contains protein B-100. In the capillaries, TAGs are hydrolyzed by LpL and they exchange TAG for cholesterol esters from high-density lipoproteins (HDLs). VLDLs are converted to intermediate density lipoproteins (IDLs). TAGs are hydrolyzed by liver lipase, apo E returns to HDL. Hepatocytes remove more than 50% of IDL from the circulation. The rest are the low density density lipoproteins (LDLs), rich in Chol. All cells have receptors that bind B-100 and internalize LDL composed of apos B-100 and E, Chol, mostly CholE, and low proportion of TAG. (3) HDLs are synthesized in the liver and intestine and contain apo A, C, and E, lecithin-cholesterol acyltransferase (LCAT) and phospholipids. In blood, HDL donates apo C and E to VLDL and chylomicrons. In extrahepatic tissues, HDL binds to the capillary endothelium and receives cholesterol from the cells, which is esterified by LCAT and transferred to VLDL and chylomicrons (reverse cholesterol transport). Remnants of these particles are taken up by the liver. Fat metabolism starts with the hydrolysis of TAG into glycerol (Glyc) and FA, by the action of intracellular lipase and LpL. Glycerol is converted into glyceraldehyde-3-P that can be directed to glycolysis or gluconeogenesis. FAs are catabolyzed in mitochondria by β-oxidation. β-oxidation follows a series of oxidative steps and the release of acyl-CoA. Ketogenesis produces ketone bodies from acetoacetate, 3-OH butyrate, and acetone. Muscle, heart, and other tissues are capable of activating acetoacetate and can use ketone bodies as fuel; the liver cannot. FA biosynthesis takes place from acetyl-CoA (generated mainly by degradation of glucose and amino acid carbon chains) by the FA synthase multienzyme system. Essential polyunsaturated FA cannot be synthesized, they must be obtained from the diet. Eicosanoids (prostaglandins, thromboxanes, and leukotrienes) are synthesized from arachidonic acid and catalyzed by cyclo-oxigenase. Biosynthesis of triacylglycerols (TAG) starts with the activation of glycerol to glycerol-3-P and FAs to acyl-CoA. Glycerol-3-phosphate is esterified at carbons 1 and 2 by two acyl groups transferred from acyl-CoA to form 1,2-diacylglycerolphosphate, also called phosphatidic acid. A new acyl-CoA molecule transfers another acyl to 1,2-diacylglycerol and triacylglycerol is produced. Phospholipids in higher animals are synthesized from phosphatidic acid. Cholesterol synthesis comprises three stages: acetate to mevalonate, mevalonate to squalene, and squalene to Chol. It is removed from plasma by LDL receptors in all cells. Bile acids and steroid hormones are synthesized from cholesterol.

Background We hypothesized that adolescents with obesity have higher remnant B48 concentrations associated with lipoprotein lipase dysregulation. Methods Cross-sectional study of 32 adolescents with obesity and 27 control subjects. Results As compared to lean controls, obese participants showed 35% higher concentrations of apoB48: 3.60 (2.93–4.30) vs 2.65 (1.64–3.68) ng/ml; 28% of apoC-III: (72.7 (58.6–89.7) vs 56.9 (44.8–79.8 ug/ml and 17% ANGPTL 3: (72.2 ± 20.2 vs 61.2 ± 19.2 ng/ml). This was accompanied by a 33% reduction in LPL: 13.1 ± 5.1 vs 18.9 ± 4.7 ng/ml. Obese participants had 25% lower adiponectin 2.9 (1.9–3.8) vs 4.4 (3.2.-5.2) μg/ml; 260% higher leptin 25.7 (11.2–44.8) vs 9.3 (2.8–20.7) ng/ml c and 83% higher Il-6: 2.2 (1.3–5.4) vs 1.2 (0.8–1.4) pg/ml. ApoC-III and ANGPTL3 correlated positively with VAI; ANGPTL3 negatively with HDL-C; LDL size and VLDL-C. ApoB48 correlated negatively with LDL-C. Conclusions Adolescents with obesity show higher ANGPTL3 compounded with increased apoC-III associated with increased CR and lower LPL mass. This is associated with inflammation and visceral fat. The significance of these findings resides in that they shed light on a mechanism for TRL dyslipidemia in adolescents: increased LPL inhibition impairs VLDL and chylomicron catabolism leading to atherogenic remnants.

Elevated triglycerides are associated with an increased risk of cardiovascular disease (CVD). Therefore, it is very important to understand the metabolism of triglyceride-rich lipoproteins (TRLs) and their atherogenic role in animal models. Using low-density lipoprotein receptor knockout (LDLR−/−) Syrian golden hamsters, this study showed that unlike LDLR−/− mice, when LDLR−/− hamsters were fed a high cholesterol high-fat diet (HFD), they had very high plasma levels of triglycerides and cholesterol. We found that LDLR−/− hamsters exhibited increased serum TRLs and the ApoB100 and 48 in these particles after being fed with HFD. Treatment with ezetimibe for 2 weeks decreased these large particles but not the LDL. In addition, ezetimibe simultaneously reduced ApoB48 and ApoE in plasma and TRLs. The expression of LRP1 did not change in the liver. These findings suggested that the significantly reduced large particles were mainly chylomicron remnants, and further, the remnants were mainly cleared by the LDL receptor in hamsters. After 40 days on an HFD, LDLR−/− hamsters had accelerated aortic atherosclerosis, accompanied by severe fatty liver, and ezetimibe treatment reduced the consequences of hyperlipidemia. Compared with the serum from LDLR−/− hamsters, that from ezetimibe-treated LDLR−/− hamsters decreased the expression of vascular adhesion factors in vascular endothelial cells and lipid uptake by macrophages. Our results suggested that in the LDLR−/− hamster model, intestinally-derived lipoprotein remnants are highly atherogenic and the inflammatory response of the endothelium and foam cells from macrophages triggered atherosclerosis. The LDL receptor might be very important for chylomicrons remnant clearance in the Syrian golden hamster, and this may not be compensated by another pathway. We suggest that the LDLR−/− hamster is a good model for the study of TRLs-related diseases as it mimics more complex hyperlipidemia.

This article reviews the literature on capillarization of hepatic sinusoids since its discovery in 1963. Liver sinusoidal endothelial cells are uniquely fenestrated and lack an underlying basement membrane. In chronic liver disease, the sinusoids capillarize and transform into systemic capillaries, a process termed capillarization of sinusoids. The histopathology is marked by defenestration, basement membrane formation, and space of Disse fibrogenesis. Capillarized sinusoids compromise the bidirectional exchange of materials between sinusoids and hepatocytes, leading to hepatocellular dysfunction. Sinusoidal capillarization was first described in active cirrhosis of alcoholics in 1963. Since then, it has been found in early and progressive stages of alcoholic hepatic fibrosis before the onset of cirrhosis. The sinusoidal structure is not altered in alcoholic steatosis without fibrosis. Defenestration impairs the ability of the endothelium to filter chylomicron remnants from sinusoids into the Disse's space, contributing to alcohol-induced postprandial hyperlipidemia and possibly atherosclerosis. Ethanol also modulates the fenestration dynamics in animals. In baboons, chronic alcohol consumption diminishes endothelial porosity in concomitance with hepatic fibrogenesis and in rats defenestrates the endothelium in the absence of fibrosis, and sometimes capillarizes the sinusoids. Acute ethanol ingestion enlarges fenestrations in rats and contracts fenestrations in rabbits. In sinusoidal endothelial cell culture, ethanol elicits fenestration dilation, which is likely related to its interaction with fenestration-associated cytoskeleton. Ethanol potentiates sinusoidal injury caused by cocaine, acetaminophen or lipopolysaccharide in mice and rats. Understanding ethanol's mechanisms on pathogenesis of sinusoidal capillarization and fenestration dynamics will lead to development of methods to prevent risks for atherosclerosis in alcoholism.

Objective: We tested the hypothesis that enlarged, dysfunctional HDL (high-density lipoprotein) particles contribute to the augmented atherosclerosis susceptibility associated with SR-BI (scavenger receptor BI) deficiency in mice. Approach and Results: We eliminated the ability of HDL particles to fully mature by targeting PLTP (phospholipid transfer protein) functionality. Particle size of the HDL population was almost fully normalized in male and female SR-BI×PLTP double knockout mice. In contrast, the plasma unesterified cholesterol to cholesteryl ester ratio remained elevated. The PLTP deficiency-induced reduction in HDL size in SR-BI knockout mice resulted in a normalized aortic tissue oxidative stress status on Western-type diet. Atherosclerosis susceptibility was—however—only partially reversed in double knockout mice, which can likely be attributed to the fact that they developed a metabolic syndrome-like phenotype characterized by obesity, hypertriglyceridemia, and a reduced glucose tolerance. Mechanistic studies in chow diet–fed mice revealed that the diminished glucose tolerance was probably secondary to the exaggerated postprandial triglyceride response. The absence of PLTP did not affect LPL (lipoprotein lipase)-mediated triglyceride lipolysis but rather modified the ability of VLDL (very low-density lipoprotein)/chylomicron remnants to be cleared from the circulation by the liver through receptors other than SR-BI. As a result, livers of double knockout mice only cleared 26% of the fractional dose of [ 14 C]cholesteryl oleate after intravenous VLDL-like particle injection. Conclusions: We have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.

Postprandial lipemia is an independent risk factor for CVD, due to effects on lipoprotein remodelling, oxidative stress, inflammation, haemostasis and endothelial dysfunction. However, it is unknown whether the total, peak or duration of the lipemic response determines risk. The PREDICT I study is the largest study to date to measure postprandial lipemic responses and intermediary acutely changing cardiometabolic risk factors at multiple time points using a standardized test meal model.A multi-center postprandial study of 1,000 individuals from the UK (unrelated, identical and non-identical twins) and 100 unrelated individuals from the US, assessed postprandial (hourly 0–6h) metabolic responses to sequential mixed-nutrient dietary challenges (50 g fat, 85 g carbohydrate at 0 h; 22 g fat, 71 g carbohydrate at 4h) in a clinic setting. We investigated the relationship of different postprandial triacylglycerol (TG) measures (4 and 6 h TG iAUC, 4 and 6 h TG concentration, 4 and 6 h TG increase from fasting) with lipoprotein remodelling (XXL-VLDL (including chylomicron remnants and VLDL particles) and XL-VLDL particle concentrations (average diameters > 75, 64 nm respectively), HDL-C) and levels of glycosylated acute phase proteins (GlycA; marker of cardiovascular inflammation), all of which have been implicated as independent predictors of CVD risk.Following adjustment (for use of medication, demographic characteristics, fasting TG, insulin and glucose levels), all six postprandial TG measures (4 and 6 h TG iAUC, 4 and 6 h TG concentration, 4 and 6 h TG increase from fasting) were strongly correlated with markers of atherogenic lipoprotein remodelling and the marker of cardiovascular inflammation (GlycA). The strongest correlation (interim analysis) was observed for the 6 h TG increase from fasting (all P < 0.001, Pearson's coefficient r = 0.94 [95%CI's; 0.93, 0.95] for XXL-VLDL-P; r = 0.95 [95%CI's; 0.95, 0.96] for XL-VLDL-P; r = 0.89 [95%CI's; 0.88, 0.91] for GlycA ; r = -0.61 [95%CI's; -0.66, -0.55] for HDL-C). Inter-individual variability in postprandial lipemic responses was high in the tightly controlled clinic setting (interim analysis, n = 656); IQR (median) was; iAUC (0–6h) 2.39 (2.31) mmol/L.h; Cmax 1.32 (2.06) mmol/L; Tmax 30.0 (300) min; and increase above fasting at 6 h 0.78 (0.62) mmol/L.This is the most detailed postprandial study performed to date and suggests that identifying predictors of the postprandial 6 h TG rise will have the highest CVD relevance. Ongoing exploration in PREDICT I of the determinants of postprandial lipemic responses considering environmental, genetic and microbiome variables will significantly advance our ability to predict an individual's postprandial response and its links to cardiovascular risk.

Supplemental Digital Content is available in the text., Objective— Studies into the role of LRP1 (low-density lipoprotein receptor–related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels. Approach and Results— In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels. Conclusions— This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.

BACKGROUND: Trapping of apoB lipoprotein particles within the arterial wall initiates and drives the atherosclerotic process from beginning to end. Very low-density lipoprotein particles (VLDL) contain most of the triglyceride in plasma whereas low-density lipoprotein particles (LDL) particles contain most of the cholesterol. Smaller numbers of chylomicron and Lp(a) particles are also present in plasma. All these particles have one molecule of apoB. Therefore, plasma apoB equals the total number of apoB particles. Because the lipid content of apoB particles is variable, plasma triglyceride and cholesterol are not always accurate-measures of the number of apoB particles. THE CHOLESTEROL MODEL OF ATHEROSCLEROSIS: The conventional model of atherosclerosis presumes that the mass of cholesterol within VLDL and LDL particles is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. But cholesterol can only enter the arterial wall within apoB particles and the mass of cholesterol that will be deposited is determined by the rate at which apoB particles are trapped within the arterial wall rather than passing harmless through. THE APOB PARTICLE MODEL OF ATHEROGENESIS: The number of apoB particles that enter and are trapped within the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. If so, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle. By contrast, more smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and Lp(a), all apoB particles are equally atherogenic. ApoB, therefore, unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins.