Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion.

BACKGROUND AND AIMS: The assembly and secretion of VLDL from the liver, a pathway that affects hepatic and plasma lipids, remains incompletely understood. We set out to identify players in the VLDL biogenesis pathway by identifying genes that are co-expressed with the MTTP gene that encodes for microsomal triglyceride transfer protein, key to the lipidation of apolipoprotein B, the core protein of VLDL. Using human and murine transcriptomic data sets, we identified small leucine-rich protein 1 ( SMLR1 ), encoding for small leucine-rich protein 1, a protein of unknown function that is exclusively expressed in liver and small intestine. APPROACH AND RESULTS: To assess the role of SMLR1 in the liver, we used somatic CRISPR/CRISPR-associated protein 9 gene editing to silence murine Smlr1 in hepatocytes ( Smlr1 -LKO). When fed a chow diet, male and female mice show hepatic steatosis, reduced plasma apolipoprotein B and triglycerides, and reduced VLDL secretion without affecting microsomal triglyceride transfer protein activity. Immunofluorescence studies show that SMLR1 is in the endoplasmic reticulum and Cis-Golgi complex. The loss of hepatic SMLR1 in female mice protects against diet-induced hyperlipidemia and atherosclerosis but causes NASH. On a high-fat, high-cholesterol diet, insulin and glucose tolerance tests did not reveal differences in male Smlr1 -LKO mice versus controls. CONCLUSIONS: We propose a role for SMLR1 in the trafficking of VLDL from the endoplasmic reticulum to the Cis-Golgi complex. While this study uncovers SMLR1 as a player in the VLDL assembly, trafficking, and secretion pathway, it also shows that NASH can occur with undisturbed glucose homeostasis and atheroprotection.

Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis.

AIMS: Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive. METHODS AND RESULTS: Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to up-regulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity, and increased atherosclerotic plaque stability index. CONCLUSION: FGF21 improves hypercholesterolaemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease.

Celecoxib exhibits therapeutic potential in experimental model of hyperlipidaemia.

Hyperlipidaemia is a major risk factor for cardiovascular diseases, the leading cause of death globally. Celecoxib attenuated hypercholesterolaemia associated with CCl4-induced hepatic injury in rats without improving liver function in our previous study. This present study investigated the lipid lowering potential of celecoxib in normal rats fed with coconut oil subjected to five deep-frying episodes. Male Sprague Dawley rats were randomly assigned to groups (n = 6 rats/group) which received physiological saline (10 mL/kg), unheated coconut oil (UO, 10 mL/kg) or heated coconut oil (HO, 10 ml/kg) for 60 days. Groups that received HO were subsequently treated with either physiological saline, atorvastatin (25 mg/kg), celecoxib (5 mg/kg) or celecoxib (10 mg/kg) in the last fifteen days of the experiment. Rats were sacrificed 24 hours after last treatment and blood and tissue samples collected for analysis. HO consumption produced significant hyperlipidaemia and elevation in marker enzymes of hepatic function. Celecoxib ameliorated the hyperlipidaemia as shown by the significantly (P<0.05) lower total cholesterol, triglycerides, low and very low density lipoprotein in the celecoxib-treated rats when compared with HO-fed rats that received saline. Celecoxib also reduced (P<0.05) alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and liver weight of hyperlipidaemic rats. Similarly, hepatocellular damage with the hyperlipidaemia was significantly reversed by celecoxib. However, serum TNF-α and IL-6 did not change significantly between the various groups. Taken together, data from this study suggest that celecoxib may exert therapeutic benefit in hyperlipidaemia and its attendant consequences.

Associations between serum lipids and mannose levels in coronary artery disease among nondiabetic patients.

Aim: Nondiabetic patients have been studied to determine whether modest elevations in plasma mannose levels may be associated with a greater incidence of coronary artery disease (CAD). Materials & methods: The plasma mannose, lipids (triglyceride, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein) and lactate dehydrogenase levels were successfully evaluated with respect to subsequent CAD using records of 120 nondiabetic patients and 120 healthy volunteers. CAD was identified from myocardial infarction and new diagnoses of angina. Results: Of 120 patients studied, the plasma mannose, triglyceride, lactate dehydrogenase and very low-density lipoprotein levels of patients were significantly higher than control groups. Conclusion: Our findings showed that elevated baseline mannose in plasma was associated with a progressive risk of CAD with time.

Agomelatine reduces circulating triacylglycerides and hepatic steatosis in fructose-treated rats.

Agomelatine (AGO) is an antidepressant drug with agonistic activity at melatonin receptor 1 (MT1) and MT2 and with neutral antagonistic activity at serotonin receptor 5-HT2C. Although experimental studies show that melatonin reduces hypertriglyceridemia and hepatic steatosis induced by excessive fructose intake, no studies have tested if AGO exerts similar actions. To address this issue we have treated male Wistar rats with fructose (15% in the drinking water) and/or AGO (40 mg/kg/day) for two weeks. AGO reduced body weight gain, feeding efficiency and hepatic lipid levels without affecting caloric intake in fructose-treated rats. AGO has also decreased very low-density lipoprotein (VLDL) production and circulating TAG levels after an oral load with olive oil. Accordingly, treatment with AGO reduced the hepatic expression of fatty acid synthase (Fasn), a limiting step for hepatic de novo lipogenesis (DNLG). The expression of apolipoprotein B (Apob) and microsomal triglyceride transfer protein (Mttp) in the ileum, two crucial proteins for intestinal lipoprotein production, were also downregulated by treatment with AGO. Altogether, the present data show that AGO mimics the metabolic benefits of melatonin when used in fructose-treated rats. This study also suggests that it is relevant to evaluate the potential of AGO to treat metabolic disorders in future clinical trials.

Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model.

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE-/-) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

Decreased Efficiency of Very-Low-Density Lipoprotein Lipolysis Is Linked to Both Hypertriglyceridemia and Hypercholesterolemia, but It Can Be Counteracted by High-Density Lipoprotein.

Impaired triglyceride-rich lipoprotein plasma catabolism is considered the most important factor for hypertriglyceridemia development. The aim of this study was to evaluate the impact of hypercholesterolemia and hypertriglyceridemia on the efficiency of lipoprotein lipase (LPL)-mediated very-low-density lipoprotein (VLDL)-triglyceride lipolysis and the role of high-density lipoprotein (HDL) in this process. Subjects with no history of cardiovascular disease (CVD) and untreated with lipid-lowering agents were recruited into the study and divided into normolipidemic, hypercholesterolemic, and hyperlipidemic groups. VLDL was isolated from serum and incubated with LPL in the absence or presence of HDL. For the hypercholesterolemic and hyperlipidemic groups, a significantly lower percentage of hydrolyzed VLDL-triglyceride was achieved compared to the normolipidemic group (p < 0.01). HDL enhanced the lipolysis efficiency in the hypercholesterolemic and hyperlipidemic groups on average by ~7% (p < 0.001). The lowest electrophoretic mobility of the VLDL remnants indicating the most effective lipolysis was obtained in the normolipidemic group (p < 0.05). HDL presence significantly reduced the electrophoretic mobility of the VLDL remnants for the hypercholesterolemic and hyperlipidemic groups (p < 0.05). The results of our study indicate that VLDL obtained from hypercholesterolemic and hyperlipidemic subjects are more resistant to lipolysis and are additional evidence of the need for early implementation of hypocholesterolemic treatment, already in asymptomatic CVD subjects.

Per-Particle Triglyceride-Rich Lipoproteins Imply Higher Myocardial Infarction Risk Than Low-Density Lipoproteins: Copenhagen General Population Study.

[Figure: see text].

Metabolic-associated fatty liver disease and lipoprotein metabolism.

BACKGROUND: Non-alcoholic fatty liver disease, or as recently proposed 'metabolic-associated fatty liver disease' (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, and eventually end-stage liver diseases. MAFLD is closely related to disturbances in systemic energy metabolism, including insulin resistance and atherogenic dyslipidemia. SCOPE OF REVIEW: The liver is the central organ in lipid metabolism by secreting very low density lipoproteins (VLDL) and, on the other hand, by internalizing fatty acids and lipoproteins. This review article discusses recent research addressing hepatic lipid synthesis, VLDL production, and lipoprotein internalization as well as the lipid exchange between adipose tissue and the liver in the context of MAFLD. MAJOR CONCLUSIONS: Liver steatosis in MAFLD is triggered by excessive hepatic triglyceride synthesis utilizing fatty acids derived from white adipose tissue (WAT), de novo lipogenesis (DNL) and endocytosed remnants of triglyceride-rich lipoproteins. In consequence of high hepatic lipid content, VLDL secretion is enhanced, which is the primary cause of complex dyslipidemia typical for subjects with MAFLD. Interventions reducing VLDL secretory capacity attenuate dyslipidemia while they exacerbate MAFLD, indicating that the balance of lipid storage versus secretion in hepatocytes is a critical parameter determining disease outcome. Proof of concept studies have shown that promoting lipid storage and energy combustion in adipose tissues reduces hepatic lipid load and thus ameliorates MAFLD. Moreover, hepatocellular triglyceride synthesis from DNL and WAT-derived fatty acids can be targeted to treat MAFLD. However, more research is needed to understand how individual transporters, enzymes, and their isoforms affect steatosis and dyslipidemia in vivo, and whether these two aspects of MAFLD can be selectively treated. Processing of cholesterol-enriched lipoproteins appears less important for steatosis. It may, however, modulate inflammation and consequently MAFLD progression.

LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability.

The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show that Lzp deletion inhibited very low-density lipoprotein (VLDL) secretion, leading to hepatic TG accumulation and lower serum TG levels in mice. The apolipoprotein B (apoB) levels were significantly decreased in the liver, serum, and VLDL particles of LZP-deficient mice. In the presence of LZP, which is localized to the endoplasmic reticulum (ER) and Golgi apparatus, the ER-associated degradation (ERAD) of apoB was attenuated; in contrast, in the absence of LZP, apoB was ubiquitinated by AMFR, a known E3 ubiquitin ligase specific for apoB, and was subsequently degraded, leading to lower hepatic apoB levels and inhibited VLDL secretion. Interestingly, hepatic LZP levels were elevated in mice challenged with a high-fat diet and humans with simple hepatic steatosis, suggesting that LZP contributes to the physiological regulation of hepatic TG homeostasis. In general, our data establish an essential role for LZP in hepatic TG transportation and VLDL secretion by preventing the AMFR-mediated ubiquitination and degradation of apoB and therefore provide insight into the molecular function of LZP in hepatic lipid metabolism.

Association of serum VLDL level with hyperhomocysteinemia in hypertensive patients: A cross-sectional study.

BACKGROUND: Increasing evidence suggests that hyperhomocysteinemia (HHcy) and hyperlipidemia have been recognized as two independent risks for cardiovascular disease. However, the association between hyperlipidemia and HHcy in hypertensive patients has not been systemically elucidated. The aim of this study was to investigate the relation between very low-density lipoprotein (VLDL) and HHcy in hypertensive patients. METHODS: From July 2013 to March 2014, a large cross-sectional study was performed using 4012 participants from urban and rural communities in Hunan province, China. Participants underwent accurate assessment of lipid profiles, homocysteine (Hcy), anthropometric, blood pressure, and other biochemical indicators. RESULTS: Among 1257 participants with hypertension, 626 (49.80%) were men and 631 (50.20%) were women. In total, 1081 (86.00%) of the participants were found to have HHcy, of which 559 (44.47%) were men and 522 (41.53%) were women. In the univariate analysis, the OR for patients with hypertension associated with hyperhomocysteinemia was significantly enhanced as the quartiles of the Log VLDL were increased. OR for quartile 4 was significantly higher than that for quartile 1 (OR = 3.7, 95% CI: 2.6-5.1; P< .001). Additional adjustment for the confounding variables did not reduce the ORs for the association between the Log VLDL and hypertension associated with hyperhomocysteinemia (OR = 3.8, 95% CI: 2.7-5.5; P< .001; OR = 4.3, 95% CI: 1.6-11.8; P= .004, respectively). We also conducted analyses with Log VLDL as a continuous variable. Each unit increase in the Log VLDL was associated with the 1.3-fold increased risk of hypertension associated with hyperhomocysteinemia (95% CI: 1.9-2.9; P< .001). Adjusting for Cr, TG, TC, and HDL did not affect the relationship. CONCLUSIONS: Our data indicate that the Log VLDL concentrations appear to be an independent contributor to hypertension associated with hyperhomocysteinemia, even after adjusting for age and other covariables. The utility of the Log VLDL as a diagnostic, prognostic, and therapeutic indicator for the disease warrants further investigation. ABBREVIATIONS: HHcy: hyperhomocysteinemia; Hcy: homocysteine; VLDL: very low-density lipoprotein; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; ALT: alanine aminotransferase; Cr: creatinine; UA: uric acid; TG: triglycerides; TC: total cholesterol; HDL: high-density lipoprotein; LDL: low-density lipoprotein; FBG: fasting blood glucose; CRP: C-reactive protein; MTHFR: methylene tetrahydrofolate reductase; NO: nitric oxide; HDL-C: high-density lipoprotein cholesterol.

A homogeneous assay to determine high-density lipoprotein subclass cholesterol in serum.

Existing methods to measure high-density lipoprotein cholesterol (HDL-C) subclasses (HDL2-C and HDL3-C) are complex and require proficiency, and thus there is a need for a convenient, homogeneous assay to determine HDL-C subclasses in serum. Here, cholesterol reactivities in lipoprotein fractions [HDL2, HDL3, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL)] toward polyethylene glycol (PEG)-modified enzymes were determined in the presence of varying concentrations of dextran sulfate and magnesium nitrate. Particle sizes formed in the lipoprotein fractions were measured by dynamic light scattering. We optimized the concentrations of dextran sulfate and magnesium nitrate before assay with PEG-modified enzymes to provide selectivity for HDL3-C. On addition of dextran sulfate and magnesium nitrate, the sizes of particles of HDL2, LDL, and VLDL increased, but the size of HDL3 fraction particles remained constant, allowing only HDL3-C to participate in coupled reactions with the PEG-modified enzymes. In serum from both healthy volunteers and patients with type 2 diabetes, a good correlation was observed between the proposed assay and ultracentrifugation in the determination of HDL-C subclasses. The assay proposed here enables convenient and accurate determination of HDL-C subclasses in serum on a general automatic analyzer and enables low-cost routine diagnosis without preprocessing.

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Increased particle size of triacylglycerol-enriched remnant lipoproteins, but not their plasma concentration or lipid content, augments risk prediction of incident type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes prevention requires the accurate identification of those at high risk. Beyond the association of fasting serum triacylglycerols with diabetes, triacylglycerol-enriched remnant lipoproteins (TRLs) more accurately reflect pathophysiological changes that underlie progression to diabetes, such as hepatic insulin resistance, pancreatic steatosis and systemic inflammation. We hypothesised that TRL-related factors could improve risk prediction for incident diabetes. METHODS: We included individuals from the Brazilian Longitudinal Study of Adult Health cohort. We trained a logistic regression model for the risk of incident diabetes in 80% of the cohort using tenfold cross-validation, and tested the model in the remaining 20% of the cohort (test set). Variables included medical history and traits of the metabolic syndrome, followed by TRL-related measurements (plasma concentration, TRL particle diameter, cholesterol and triacylglycerol content). TRL features were measured using NMR spectroscopy. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). RESULTS: Among 4463 at-risk individuals, there were 366 new cases of diabetes after a mean (±SD) of 3.7 (±0.63) years of follow-up. We derived an 18-variable model with a global AUROC of 0.846 (95% CI: 0.829, 0.869). Overall TRL-related markers were not associated with diabetes. However, TRL particle diameter increased the AUROC, particularly in individuals with HbA1c <39 mmol/mol (5.7%) (hold-out test set [n = 659]; training-validation set [n = 2638]), but not in individuals with baseline HbA1c 39-46 mmol/mol (5.7-6.4%) (hold-out test set [n = 233]; training-validation set [n = 933]). In the subgroup with baseline HbA1c <39 mmol/mol (5.7%), AUROC in the test set increased from 0.717 (95% CI 0.603, 0.818) to 0.794 (95% CI 0.731, 0.862), and AUPRC in the test set rose from 0.582 to 0.701 when using the baseline model and the baseline model plus TRL particle diameter, respectively. TRL particle diameter was highly correlated with obesity, insulin resistance and inflammation in those with impaired fasting glucose at baseline, but less so in those with HbA1c <39 mmol/mol (5.7%). CONCLUSIONS/INTERPRETATION: TRL particle diameter improves the prediction of diabetes, but only in individuals with HbA1c <39 mmol/mol (5.7%) at baseline. These data support TRL particle diameter as a risk factor that is changed early in the course of the pathophysiological processes that lead to the development of type 2 diabetes, even before glucose abnormalities are established. Graphical abstract.

Dihydroceramides in Triglyceride-Enriched VLDL Are Associated with Nonalcoholic Fatty Liver Disease Severity in Type 2 Diabetes.

Plasma dihydroceramides are predictors of type 2 diabetes and related to metabolic dysfunctions, but the underlying mechanisms are not characterized. We compare the relationships between plasma dihydroceramides and biochemical and hepatic parameters in two cohorts of diabetic patients. Hepatic steatosis, steatohepatitis, and fibrosis are assessed by their plasma biomarkers. Plasma lipoprotein sphingolipids are studied in a sub-group of diabetic patients. Liver biopsies from subjects with suspected non-alcoholic fatty liver disease are analyzed for sphingolipid synthesis enzyme expression. Dihydroceramides, contained in triglyceride-rich very-low-density lipoprotein (VLDL), are associated with steatosis and steatohepatitis. Expression of sphingolipid synthesis enzymes is correlated with histological steatosis and inflammation grades. In conclusion, association of plasma dihydroceramides with nonalcoholic fatty liver might explain their predictive character for type 2 diabetes. Our results suggest a relationship between hepatic sphingolipid metabolism and steatohepatitis and an involvement of dihydroceramides in the synthesis/secretion of triglyceride-rich VLDL, a hallmark of NAFLD and type 2 diabetes dyslipidemia.

Plasma lipoprotein profile from nonalcoholic steatohepatitis model rats.

We recently revealed that increases in particle sizes of very-low-density lipoproteins (VLDL) are highly correlated with the progression of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), and VLDL particle size may be a minimally invasive indicator of these hepatic disorders. Methionine and choline-deficient (MCD) diet fed animals are usually used as a NASH model; however, the application of this minimally invasive biomarker in MCD diet fed animals remains unclear. In the present study, we measured the levels of liver disease markers and plasma lipoprotein profiles in MCD diet fed rats, and compared them with those of normal diet fed rats. Assessing lipoprotein profiles showed marked increases in VLDL particle sizes in MCD diet fed rats with pathologically and biochemically NASH-like features.

VLDL Cholesterol Accounts for One-Half of the Risk of Myocardial Infarction Associated With apoB-Containing Lipoproteins.

BACKGROUND: Plasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs). OBJECTIVES: The authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins. METHODS: Nested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs). RESULTS: During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk. CONCLUSIONS: VLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.

In pregnancy, maternal HDL is specifically enriched in, and carries the highest proportion of, DHA in plasma.

Arachidonic acid (AA) and docosahexaenoic acid (DHA) are important for neurological development. The aim was to determine the distribution and relative enrichment of AA and DHA among lipoprotein fractions prior to pregnancy, throughout gestation and in the post-partum period. Our hypothesis was that in pregnancy, in contrast to the non-pregnant state, AA and DHA are carried in highest concentration in the very low density lipoprotein (VLDL) fraction secondary to increased gestational liver triglyceride secretion. Two independent prospective, observational cohort studies carried out in Glasgow were combined; one early in pregnancy and one later in pregnancy with post-partum follow up. Across the pregnancy timeline plasma lipoproteins were isolated using sequential ultracentrifugation and lipoprotein fatty acids were extracted and analysed by gas chromatography. High density lipoprotein (HDL) had the highest concentration of AA and DHA compared to other lipoproteins. HDL became progressively enriched in the proportion of triglycerides at 16 weeks of gestation, which peaked at 35 weeks and returned to baseline at 13 weeks postpartum. HDL DHA per HDL-cholesterol and HDL DHA per apoA-I became progressively enriched at 16 weeks of gestation, peaked at 25 weeks and returned to baseline at 13 weeks postpartum, whereas HDL AA (per HDL-C or HDL-apoA-I) did not differ. DHA is carried primarily in HDL rather than VLDL. HDL has anti-oxidant properties that might afford DHA protection against oxidation.

Features of Myocardial Remodeling and Changes in the Blood Lipid Spectrum in Experimental Doxorubicin-Induced Cardiomyopathy and Atorvastatin Administration.

Structural myocardial reorganization and changes in the blood lipid spectrum in rats were studied after administration of a single sublethal dose of doxorubicin (15 mg/kg) alone and in combination with atorvastatin (20 mg/kg/day over 7 days). It was established that doxorubicin induced the development of dyslipidemia in experimental animals (the concentrations of total cholesterol, triglycerides, and VLDL increased by 2.2, 2.0, and 1.96 times, respectively; the atherogenic coefficient increased by 3.4 times by day 7 of the experiment). In animals with experimental anthracycline cardiomyopathy treated with atorvastatin, the concentrations of the main components of the blood lipid spectrum increased less markedly. Atorvastatin alone induces moderate myocardial remodeling in comparison with more pronounced changes in the structural organization of the myocardium in rats treated with doxorubicin alone. Course treatment with atorvastatin under conditions of doxorubicin-induced cardiomyopathy reduced the severity of myocardial remodeling: the decrease in the volume density of cardiomyocytes and the increase in the volume density of the connective tissue were less pronounced in the dynamics of the experiment.