Being overweight increases the risk of the development of metabolic conditions such as non-alcoholic fatty liver disease (NAFLD), which is itself an independent predictor of cardiovascular disease. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is recommended for prevention of chronic disease, and is thought to reduce raised liver fat, yet there have been few randomized controlled trials with accurate measurement of liver fat. We assessed the effect of 12 weeks of supplementation with omega-3 PUFA from fish oil versus placebo on quantified liver fat, liver tests, and body composition including visceral adipose tissue (VAT) in a double-blind randomized controlled trial. Fifty apparently healthy overweight men (BMI 25.0–29.9 kg/m2; waist > 94 cm) were randomly allocated to consume fish oil (total daily dose: 1728 mg marine triglycerides, of which 588 mg EPA and 412 mg DHA, combined with 200 mg antioxidant, coenzyme Q10) or placebo (olive oil capsules) daily for 12 weeks. Liver fat was assessed using proton magnetic resonance spectroscopy. All outcomes were assessed at baseline and following 6 and 12 weeks of supplementation. Baseline liver fat was 4.6 ± 0.5% (range: 0.6 to 18.2%); 16 (32%) participants met the criteria for NAFLD (>5.5% liver fat). Repeated measures ANOVA revealed no significant time or group × time effect for fish oil versus placebo for liver fat, liver enzymes, anthropometry, or body composition including VAT (p > 0.05 for all), with similar finding for sub-analysis of participants with NAFLD. Omega-3 PUFA did not appear to be an effective agent for reducing liver fat in overweight men. The factors determining the health benefits of omega-3 PUFA supplementation on an individual level need to be clarified.

Non-alcoholic fatty liver disease (NAFLD) is an independent predictor of CVD in otherwise healthy individuals. Low n-3 PUFA intake has been associated with the presence of NAFLD; however, the relationship between a biomarker of n-3 status - the Omega-3 Index - and liver fat is yet to be elucidated. A total of eighty overweight adults (fifty-six men) completed the anthropometric and biochemical measurements, including the Omega-3 Index, and underwent proton magnetic resonance spectroscopy assessment of liver fat. Bivariate correlations and multiple regression analyses were performed with reference to prediction of liver fat percentage. The mean Omega-3 Index was high in both NAFLD (intrahepatic lipid concentration≥5·5 %) and non-NAFLD groups. The Omega-3 Index, BMI, waist circumference, glucose, insulin, TAG, high-sensitive C-reactive protein (hsCRP) and alanine aminotransferase (ALT) were positively correlated, and HDL and erythrocyte n-6:n-3 ratio negatively correlated with liver fat concentration. Regression analysis found that simple anthropometric and demographic variables (waist, age) accounted for 31 % of the variance in liver fat and the addition of traditional cardiometabolic blood markers (TAG, HDL, hsCRP and ALT) increased the predictive power to 43 %. The addition of the novel erythrocyte fatty acid variable (Omega-3 Index) to the model only accounted for a further 3 % of the variance (P=0·049). In conclusion, the Omega-3 Index was associated with liver fat concentration but did not improve the overall capacity of demographic, anthropometric and blood markers to predict NAFLD.

PURPOSE Health care leaders encourage clinicians to offer portals that enable patients to access personal health records, but implementation has been a challenge. Although large integrated health systems have promoted use through costly advertising campaigns, other implementation methods are needed for small to medium-sized practices where most patients receive their care.METHODS We conducted a mixed methods assessment of a proactive implementation strategy for a patient portal (an interactive preventive health record [IPHR]) offered by 8 primary care practices. The practices implemented a series of learning collaboratives with practice champions and redesigned workflow to integrate portal use into care. Practice implementation strategies, portal use, and factors influencing use were assessed prospectively.RESULTS A proactive and customized implementation strategy designed by practices resulted in 25.6% of patients using the IPHR, with the rate increasing 1.0% per month over 31 months. Fully 23.5% of IPHR users signed up within 1 day of their office visit. Older patients and patients with comorbidities were more likely to use the IPHR, but blacks and Hispanics were less likely. Older age diminished as a factor after adjusting for comorbidities. Implementation by practice varied considerably (from 22.1% to 27.9%, P <.001) based on clinician characteristics and workflow innovations adopted by practices to enhance uptake.CONCLUSIONS By directly engaging patients to use a portal and supporting practices to integrate use into care, primary care practices can match or potentially surpass the usage rates achieved by large health systems.

Controlling intestinal lipid absorption is an important strategy for maintaining lipid homeostasis. Accumulation of lipids in the liver is a major risk factor for metabolic syndrome and nonalcoholic fatty liver disease. It is well-known that sphingomyelin (SM) can inhibit intestinal cholesterol absorption. It is, however, unclear if dietary SM also lowers liver lipid levels. In the present study (i) the effect of pure dietary egg SM on hepatic lipid metabolism and intestinal cholesterol absorption was measured with [(14)C]cholesterol and [(3)H]sitostanol in male C57BL/6 mice fed a high-fat (HF) diet with or without 0.6% wt/wt SM for 18 days; and (ii) hepatic lipid levels and gene expression were determined in mice given a HF diet with or without egg SM (0.3, 0.6 or 1.2% wt/wt) for 4 weeks. Mice supplemented with SM (0.6% wt/wt) had significantly increased fecal lipid and cholesterol output and reduced hepatic [(14)C]cholesterol levels after 18 days. Relative to HF-fed mice, SM-supplemented HF-fed mice had significantly lower intestinal cholesterol absorption (-30%). Liver weight was significantly lower in the 1.2% wt/wt SM-supplemented mice (-18%). Total liver lipid (mg/organ) was significantly reduced in the SM-supplemented mice (-33% and -40% in 0.6% wt/wt and 1.2% wt/wt SM, respectively), as were triglyceride and cholesterol levels. The reduction in liver triglycerides was due to inactivation of the LXR-SREBP-1c pathway. In conclusion, dietary egg SM has pronounced hepatic lipid-lowering properties in mice maintained on an obesogenic diet.

Non-alcoholic fatty liver disease (NAFLD) is a frequent accompaniment of obesity and insulin resistance. With the prevalence approaching 85% in obese populations, new therapeutic approaches to manage NAFLD are warranted. A systematic search of the literature was conducted for studies pertaining to the effect of omega-3 polyunsaturated fatty acid (PUFA) supplementation on NAFLD in humans. Primary outcome measures were liver fat and liver function tests: alanine aminotransferase (ALT) and aspartate aminotransferase [1]. Data were pooled and meta-analyses conducted using a random effects model. Nine eligible studies, involving 355 individuals given either omega-3 PUFA or control treatment were included. Beneficial changes in liver fat favoured PUFA treatment (effect size=-0.97, 95% CI: -0.58 to -1.35, p<0.001). A benefit of PUFA vs. control was also observed for AST (effect size=-0.97, 95% CI: -0.13 to -1.82, p=0.02). There was a trend towards favouring PUFA treatment on ALT but this was not significant (effect size=-0.56, 95% CI: -1.16 to 0.03, p=0.06). Sub-analyses of only randomised control trials (RCTs) showed a significant benefit for PUFA vs. control on liver fat (effect size=-0.96, 95% CI: -0.43 to -1.48, p<0.001), but not for ALT (p=0.74) or AST (p=0.28). There was significant heterogeneity between studies. The pooled data suggest that omega-3 PUFA supplementation may decrease liver fat, however, the optimal dose is currently not known. Well designed RCTs which quantify the magnitude of effect of omega-3 PUFA supplementation on liver fat are needed.

Background: Accumulating evidence suggests that tissue sphingolipids such as sphingomyelin (SM) and ceramide contribute to the onset and development of atherosclerosis. Dietary sphingolipids may not however be pathogenic and we have shown that a phospholipid-rich extract from dairy milk that contains SM has potent liver lipid-lowering properties. Objective: To investigate the effect of pure dietary egg SM on hepatic lipid metabolism in high-fat fed mice. Methods: Four groups of male C57BL/6 mice were given a high-fat diet containing 21% w/w butterfat and 0.15% w/w cholesterol (HF) or the HF diet supplemented with egg SM (0.3, 0.6 or 1.2% w/w). After 4 weeks, livers were analysed for lipid and mRNA. Intestinal cholesterol absorption was measured with [14C]cholesterol and [3H]sitostanol in mice fed 0.6% w/w SM for three weeks. Results: All animals weighed similarly. Liver weight was significantly lower in 1.2%-fed mice (HF vs SM: 1.05 ± 0.03 v 0.86 ± 0.03 g, P < 0.05 by ANOVA). Total liver lipid (mg/organ) was significantly less in 0.6%SM- and 1.2%SM-fed mice (-33% and -40% vs HF resp., P < 0.001). This was due to significantly reduced levels of both triglyceride and cholesterol. Mice given 0.6%SM for 3 weeks were found to have significantly increased faecal lipid and cholesterol output and reduced liver accumulation of gastrically-administered [14C]cholesterol. Intestinal cholesterol absorption was significantly reduced by 0.6%SM supplementation (HF vs SM: 52.4 ± 2.6 vs 36.2 ± 3.5%, P < 0.01). Conclusion: Dietary egg sphingomyelin has pronounced lipid-lowering properties, suggesting it may have atheroprotective rather than atherogenic properties.

BACKGROUND:There is substantial interest in chocolate and flavan-3-ols for the prevention of cardiovascular disease (CVD). OBJECTIVE:The objective was to systematically review the effects of chocolate, cocoa, and flavan-3-ols on major CVD risk factors. DESIGN:We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) of chocolate, cocoa, or flavan-3-ols. We contacted authors for additional data and conducted duplicate assessment of study inclusion, data extraction, validity, and random-effects meta-analyses. RESULTS:We included 42 acute or short-term chronic (≤18 wk) RCTs that comprised 1297 participants. Insulin resistance (HOMA-IR: -0.67; 95% CI: -0.98, -0.36) was improved by chocolate or cocoa due to significant reductions in serum insulin. Flow-mediated dilatation (FMD) improved after chronic (1.34%; 95% CI: 1.00%, 1.68%) and acute (3.19%; 95% CI: 2.04%, 4.33%) intakes. Effects on HOMA-IR and FMD remained stable to sensitivity analyses. We observed reductions in diastolic blood pressure (BP; -1.60 mm Hg; 95% CI: -2.77, -0.43 mm Hg) and mean arterial pressure (-1.64 mm Hg; 95% CI: -3.27, -0.01 mm Hg) and marginally significant effects on LDL (-0.07 mmol/L; 95% CI: -0.13, 0.00 mmol/L) and HDL (0.03 mmol/L; 95% CI: 0.00, 0.06 mmol/L) cholesterol. Chocolate or cocoa improved FMD regardless of the dose consumed, whereas doses >50 mg epicatechin/d resulted in greater effects on systolic and diastolic BP. GRADE (Grading of Recommendations, Assessment, Development and Evaluation, a tool to assess quality of evidence and strength of recommendations) suggested low- to moderate-quality evidence of beneficial effects, with no suggestion of negative effects. The strength of evidence was lowered due to unclear reporting for allocation concealment, dropouts, missing data on outcomes, and heterogeneity in biomarker results in some studies. CONCLUSIONS:We found consistent acute and chronic benefits of chocolate or cocoa on FMD and previously unreported promising effects on insulin and HOMA-IR. Larger, longer-duration, and independently funded trials are required to confirm the potential cardiovascular benefits of cocoa flavan-3-ols.

AIMS Plasma concentrations of high-density lipoprotein (HDL)-cholesterol correlate inversely with the incidence of myocardial infarction in humans. We investigated the effect of treatment with human apolipoprotein A-I (apoA-I), the principal protein of HDL, on plaque disruption in an animal model. METHODS AND RESULTS Seventy apolipoprotein E knockout mice were induced to develop atherosclerotic lesions in the brachiocephalic artery by feeding a high-fat diet for 9 weeks. Mice then received twice-weekly treatment with human apoA-I (8 mg/kg) or vehicle, for 2 weeks. The incidence of acute plaque disruption was reduced by 65% in mice receiving apoA-I (P < 0.01). Plaques in treated mice had a more stable phenotype, with an increase in smooth muscle cell (SMC): macrophage ratio (P = 0.05), principally the consequence of an increase in the number of SMC in plaques. In the fibrous cap, there were reductions in matrix metalloproteinase-13 (-69%, P < 0.0001) and S100A4, a marker of SMC de-differentiation (-60%, P < 0.0001). These results indicate that 2 weeks of treatment with small amounts of human apoA-I produces more stable plaques in a mouse model. CONCLUSION Treatment with apoA-I has the potential to stabilize plaques and prevent plaque rupture in humans.

Background: Triglyceride (TG) levels measured in either the fasting or non-fasting state predict the risk of cardiovascular disease (CVD). Since CVD risk assessment is affected by variability in TG, the aim of the study was to investigate intra-individual variability of non-fasting TG.Methods: Capillary triglyceride (cTG) levels were measured in 246 free-living individuals at six time-points during the day on three separate occasions. Intra-individual variability in cTG was assessed by calculating the standard deviation of three measures at each time-point. Subjects were analyzed by gender and by fasting TG level.Results: In the fasting state, intra-individual variability was similar in males and females (0.28 and 0.35 mmol/l, respectively), but increased significantly in male but not in female subjects during the day, i.e., 0.28 to 0.69, and 0.35 to 0.36 mmol/l, resp. Subjects with higher fasting TG levels had greater absolute variability in both fasting and non-fasting TG.Conclusions: The variability in non-fasting TG is greater in males and in individuals with higher levels of TG. Since greatest variability in non-fasting TG occurs very late in the day, it is unlikely to affect the assessment of CVD risk, which is based on a blood sample taken during daylight hours. (C) 2011 Elsevier B.V. All rights reserved.

Background Omega-3 polyunsaturated fatty acids (ω-3-PUFA) are known to ameliorate several metabolic risk factors for cardiovascular disease, and an association between elevated peripheral levels of endogenous ligands of cannabinoid receptors (endocannabinoids) and the metabolic syndrome has been reported. We investigated the dose-dependent effects of dietary ω-3-PUFA supplementation, given as krill oil (KO), on metabolic parameters in high fat diet (HFD)-fed mice and, in parallel, on the levels, in inguinal and epididymal adipose tissue (AT), liver, gastrocnemius muscle, kidneys and heart, of: 1) the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), 2) two anandamide congeners which activate PPARα but not cannabinoid receptors, N -oleoylethanolamine and N -palmitoylethanolamine, and 3) the direct biosynthetic precursors of these compounds. Methods Lipids were identified and quantified using liquid chromatography coupled to atmospheric pressure chemical ionization single quadrupole mass spectrometry (LC-APCI-MS) or high resolution ion trap-time of flight mass spectrometry (LC-IT-ToF-MS). Results Eight-week HFD increased endocannabinoid levels in all tissues except the liver and epididymal AT, and KO reduced anandamide and/or 2-AG levels in all tissues but not in the liver, usually in a dose-dependent manner. Levels of endocannabinoid precursors were also generally down-regulated, indicating that KO affects levels of endocannabinoids in part by reducing the availability of their biosynthetic precursors. Usually smaller effects were found of KO on OEA and PEA levels. Conclusions Our data suggest that KO may promote therapeutic benefit by reducing endocannabinoid precursor availability and hence endocannabinoid biosynthesis.

A lipid profile (LP)3 is used in clinical practice to assess risk of cardiovascular disease (CVD) and to guide therapy. The standard LP includes a direct measurement of plasma total cholesterol, triglyceride, and HDL cholesterol concentrations, and derived estimates of LDL cholesterol, non–HDL cholesterol, and lipid ratios (1). Expert guidelines recommend that accurate assessment of the LP requires a fast of 9 to 12 h (2). The principal reason is to diminish the biological variation in the plasma triglyceride concentration after ingestion of a fatty meal. Another reason is to compare plasma lipid levels with fasting data from healthy individuals. A fasting triglyceride concentration is also required for accurate estimation by the Friedewald formula of the cholesterol in LDL (3), the principal atherogenic lipoprotein. The established practice of fasting has been challenged by population studies that have shown that components of the LP, including triglycerides, do not change greatly when measured at different times during the day in nonfasting individuals (4). Compelling epidemiology data also show that nonfasting concentrations of triglycerides, LDL cholesterol, non–HDL cholesterol, and HDL cholesterol, as well as the lipid ratios, are significant predictors of cardiovascular (CV) events (5), possibly more than in the fasting state (6). Can these findings be extended to patients with type 2 diabetes, a group with a high prevalence of hypertriglyceridemia and perturbed cholesterol-rich lipoprotein metabolism (7)? Investigators from the Copenhagen General Population Study have assessed the plasma concentrations of lipids, lipoproteins, apolipoproteins, and albumin in 58 434 individuals, 2270 of whom had diabetes (8). Participants were asked the time since their last meal, and nonfasting blood samples were categorized accordingly. In individuals with and without diabetes, the plasma triglyceride concentration remained increased for up to 7 h after the last meal. A mean postprandial reduction of 0.6 mmol/L (23 …

Investigations of apoC-III metabolism using stable isotopes: what information can you acquire and how can you interpret your results?Journal of Lipid ResearchVol. 52Issue 6PreviewApolipoprotein C-III (apoC-III) is one of the "exchangeable" apolipoproteins; it is found in all of the major lipoprotein classes in varying amounts. Although the exchangeability of apoC-III has been well established and accepted, it was clear early on that this apolipoprotein, as well as several others, were not present on every lipoprotein particle (1). Moreover, work by Sacks and colleagues (2–4) has demonstrated that the metabolism of apoB-containing lipoprotein subfractions is affected by their apoC-III content. Full-Text PDF Open AccessPlasma apolipoprotein C-III metabolism in patients with chronic kidney diseaseJournal of Lipid ResearchVol. 52Issue 4PreviewModerate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30–60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, 2H3]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Full-Text PDF Open Access Apolipoprotein C-III (apoC-III) is a protein of 79 amino acids that is synthesized in the liver and to a lesser degree in the intestine (1Jong M.C. Hofker M.H. Havekes L.M. Role of apoCs in lipoprotein metabolism. Functional differences between apoC1, apoC2, and apoC3.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 472-484Crossref PubMed Scopus (437) Google Scholar). In the circulation, apoC-III is a constituent of both apoB- and apoA-I-containing lipoproteins. It is not evenly distributed between these lipoproteins however, with the majority of apoC-III found in the HDL fraction in normolipidemic individuals and on triglyceride-rich lipoproteins in patients with elevated levels of plasma triglyceride (2Fredenrich A. Giroux L.M. Tremblay M. Krimbou L. Davignon J. Cohn J.S. Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions.J. Lipid Res. 1997; 38: 1421-1432Abstract Full Text PDF PubMed Google Scholar, 3Schonfeld G. George P.K. Miller J. Reilly P. Witztum J. Apolipoprotein C-II and C-III levels in hyperlipoproteinemia.Metabolism. 1979; 28: 1001-1010Abstract Full Text PDF PubMed Scopus (145) Google Scholar). Furthermore, some VLDLs, intermediate density lipoproteins (IDLs) and LDLs contain many molecules of apoC-III, whereas others contain none (4Khoo C. Campos H. Judge H. Sacks F.M. Effects of estrogenic oral contraceptives on the lipoprotein B particle system defined by apolipoproteins E and C-III content.J. Lipid Res. 1999; 40: 202-212Abstract Full Text Full Text PDF PubMed Google Scholar). Semi-quantitative analysis suggests that less than half of apoA-I-containing lipoproteins in plasma (i.e., HDL) contain apoC-III (5Asztalos B.F. Schaefer E.J. Horvath K.V. Yamashita S. Miller M. Franceschini G. Calabresi L. Role of LCAT in HDL remodeling: investigation of LCAT deficiency states.J. Lipid Res. 2007; 48: 592-599Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). ApoC-III plays a pivotal role in regulating the plasma metabolism of VLDL, IDL, and LDL, primarily by inhibiting receptor-mediated uptake of these lipoproteins by the liver (6Sehayek E. Eisenberg S. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.J. Biol. Chem. 1991; 266: 18259-18267Abstract Full Text PDF PubMed Google Scholar, 7Aalto-Setala K. Fisher E.A. Chen X. Chajek-Shaul T. Hayek T. Zechner R. Walsh A. Ramakrishnan R. Ginsberg H.N. Breslow J.L. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.J. Clin. Invest. 1992; 90: 1889-1900Crossref PubMed Scopus (400) Google Scholar, 8Zheng C. Khoo C. Ikewaki K. Sacks F.M. Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions.J. Lipid Res. 2007; 48: 1190-1203Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). VLDL containing apoC-III are channeled down the lipolytic cascade to LDL, particularly to denser LDL that have a slower clearance rate from plasma (9Zheng C. Khoo C. Furtado J. Sacks F.M. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.Circulation. 2010; 121: 1722-1734Crossref PubMed Scopus (184) Google Scholar). ApoC-III also enhances the hepatic assembly and secretion of VLDL (10Sundaram M. Zhong S. Khalil M.B. Links P.H. Zhao Y. Iqbal J. Hussain M.M. Parks R.J. Wang Y. Yao Z. Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions.J. Lipid Res. 2010; 51: 150-161Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar), and overproduction of apoC-III and of apoB lipoproteins that contain apoC-III is a common feature of patients with hypertriglyceridemia (11Batal R. Tremblay M. Barrett P.H. Jacques H. Fredenrich A. Mamer O. Davignon J. Cohn J.S. Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects.J. Lipid Res. 2000; 41: 706-718Abstract Full Text Full Text PDF PubMed Google Scholar). Thus, apoC-III is intricately involved in establishing hypertriglyceridemia and its associated dense LDL phenotype. Much less is known, however, about the function of apoC-III when it is a component of HDL. ApoC-III has been shown to inhibit hepatic lipase (12Kinnunen P.K. Ehnolm C. Effect of serum and C-apoproteins from very low density lipoproteins on human postheparin plasma hepatic lipase.FEBS Lett. 1976; 65: 354-357Crossref PubMed Scopus (145) Google Scholar) and interact with receptors such as scavenger receptor class B type IQ1: Please confrim or amend spellouts for SR-BI and TNF. (13Xu S. Laccotripe M. Huang X. Rigotti A. Zannis V.I. Krieger M. Apolipoproteins of HDL can directly mediate binding to the scavenger receptor SR-BI, an HDL receptor that mediates selective lipid uptake.J. Lipid Res. 1997; 38: 1289-1298Abstract Full Text PDF PubMed Google Scholar) and ABCA1 (14Remaley A.T. Stonik J.A. Demosky S.J. Neufeld E.B. Bocharov A.V. Vishnyakova T.G. Eggerman T.L. Patterson A.P. Duverger N.J. Santamarina-Fojo S. Apolipoprotein specificity for lipid efflux by the human ABCAI transporter.Biochem. Biophys. Res. Commun. 2001; 280: 818-823Crossref PubMed Scopus (279) Google Scholar), thus having the potential to affect the function or metabolism of HDL. ApoC-III can also stimulate several processes involved in atherogenesis and vascular inflammation. ApoC-III stimulates blood-born monocytes and endothelial cells to produce cytokines such as tumor necrosis factor-α and adhesion molecules, and it activates insulin-resistance pathways in endothelial cells causing endothelial dysfunction (15Kawakami A. Aikawa M. Alcaide P. Luscinskas F.W. Libby P. Sacks F.M. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells.Circulation. 2006; 114: 681-687Crossref PubMed Scopus (227) Google Scholar, 16Kawakami A. Osaka M. Tani M. Azuma H. Sacks F.M. Shimokado K. Yoshida M. Apolipoprotein C-III links hyperlipidemia with vascular endothelial cell dysfunction..Circulation. 2008; 118: 731-742Crossref PubMed Scopus (73) Google Scholar). Interaction of apoC-III with TLR-2 at the cell surface acts as an initiating event in this function. ApoC-III in LDL binds to vascular proteoglycans that may lead to LDL retention in the arterial wall (17Hiukka A. Stahlman M. Pettersson C. Levin M. Adiels M. Teneberg S. Leinonen E.S. Hulten L.M. Wiklund O. Oresic M. ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan.Diabetes. 2009; 58: 2018-2026Crossref PubMed Scopus (96) Google Scholar). ApoC-III also stimulates adipocytes to produce cytokines and suppresses their production of adiponectin (18Abe Y. Kawakami A. Osaka M. Uematsu S. Akira S. Shimokado K. Sacks F.M. Yoshida M. Apolipoprotein CIII induces monocyte chemoattractant protein-1 and interleukin 6 expression via Toll-like receptor 2 pathway in mouse adipocytes.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2242-2248Crossref PubMed Scopus (20) Google Scholar). These actions, converting adipocytes into a proinflammatory phenotype, may act indirectly to promote the development of atherosclerosis. More direct evidence for the atherogenicity associated with apoC-III comes from transgenic animal studies that have found that ldlr−/− mice overexpressing human apoC-III develop enhanced atherosclerotic lesions on a Western diet (19Masucci-Magoulas L. Goldberg I.J. Bisgaier C.L. Serajuddin H. Francone O.L. Breslow J.L. Tall A.R. A mouse model with features of familial combined hyperlipidemia.Science. 1997; 275: 391-394Crossref PubMed Scopus (122) Google Scholar). Furthermore, apoC-III and the VLDL and LDL that contain it are strong independent predictors of cardiovascular events and of progression of coronary atherosclerosis (20Blankenhorn D.H. Alaupovic P. Wickham E. Chin H.P. Azen S.P. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts. Lipid and nonlipid factors.Circulation. 1990; 81: 470-476Crossref PubMed Scopus (258) Google Scholar, 21Sacks F.M. Alaupovic P. Moye L.A. Cole T.G. Sussex B. Stampfer M.J. Pfeffer M.A. Braunwald E. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.Circulation. 2000; 102: 1886-1892Crossref PubMed Scopus (415) Google Scholar). In summary, evidence from several sources link apoC-III with atherosclerosis, providing a strong rationale to better understand factors affecting the plasma metabolism of apoC-III. In the April issue of the Journal of Lipid Research, Ooi and colleagues (22Ooi E.M. Chan D.T. Watts G.F. Chan D.C. Ng T.W. Dogra G.K. Irish A.B. Barrett P.H. Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease.J. Lipid Res. 2011; 52: 794-800Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar) evaluated the metabolism of apoC-III in patients with chronic renal failure, a condition associated with a high incidence of cardiovascular disease. The principal finding was a low fractional catabolic rate (FCR) for apoC-III in VLDL of renal patients compared with controls. The FCR of VLDL apoC-III was strongly correlated with the FCR of VLDL apoB. These results provide additional evidence for an effect of apoC-III on clearance of triglyceride-rich lipoproteins and for the involvement of apoC-III in the dyslipidemia of patients with chronic renal impairment. Ooi and colleagues, in this and previous research articles (22Ooi E.M. Chan D.T. Watts G.F. Chan D.C. Ng T.W. Dogra G.K. Irish A.B. Barrett P.H. Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease.J. Lipid Res. 2011; 52: 794-800Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 23Chan D.C. Nguyen M.N. Watts G.F. Barrett P.H. Plasma apolipoprotein C-III transport in centrally obese men: associations with very low-density lipoprotein apolipoprotein B and high-density lipoprotein apolipoprotein A-I metabolism.J. Clin. Endocrinol. Metab. 2008; 93: 557-564Crossref PubMed Scopus (57) Google Scholar, 4Khoo C. Campos H. Judge H. Sacks F.M. Effects of estrogenic oral contraceptives on the lipoprotein B particle system defined by apolipoproteins E and C-III content.J. Lipid Res. 1999; 40: 202-212Abstract Full Text Full Text PDF PubMed Google Scholar), have used their apoC-III kinetic data to make general conclusions about the plasma metabolism of apoC-III. They found that their tracer enrichment-time curves for apoC-III in VLDL and in HDL were similar. Consequently, the FCR for VLDL and HDL apoC-III were the same. From this observation, they concluded that apoC-III equilibrates rapidly and completely between these lipoproteins (24Nguyen M.N. Chan D.C. Dwyer K.P. Bolitho P. Watts G.F. Barrett P.H. Use of Intralipid for kinetic analysis of HDL apoC-III: evidence for a homogeneous kinetic pool of apoC-III in plasma.J. Lipid Res. 2006; 47: 1274-1280Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Because VLDL is cleared much more rapidly from plasma than HDL, these results and conclusions suggest that apoC-III transfers or exchanges between apoB- and apoA-I-containing lipoproteins (and perhaps also between different apoB-containing subspecies), but avoids being catabolized when these lipoproteins are cleared from the circulation. This scenario would suggest that apoC-III continually "jumps off" lipoproteins before they are taken up by cells. In addition, for a one-pool model of apoC-III kinetics to adequately explain plasma apoC-III metabolism, apoC-III must be cleared as free apoC-III or as a single lipoprotein type (i.e., "terminally catabolized triglyceride-rich lipoproteins"). Because free apoC-III is not found in human plasma (5Asztalos B.F. Schaefer E.J. Horvath K.V. Yamashita S. Miller M. Franceschini G. Calabresi L. Role of LCAT in HDL remodeling: investigation of LCAT deficiency states.J. Lipid Res. 2007; 48: 592-599Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 25Krimbou L. Tremblay M. Davignon J. Cohn J.S. Characterization of human plasma apolipoprotein E-containing lipoproteins in the high density lipoprotein size range: focus on pre-beta1-LpE, pre-beta2-LpE, and alpha-LpE.J. Lipid Res. 1997; 38: 35-48Abstract Full Text PDF PubMed Google Scholar), and we find it hard to conceptualize how apoC-III escapes tissue uptake during the normal course of VLDL and HDL clearance, we have to question this oversimplified view of apoC-III metabolism. We view the one-pool model for plasma apoC-III metabolism as only one of several possible interpretations of apoC-III tracer enrichment-time curves. Ooi and colleagues have not measured the movement of apoC-III between lipoproteins, so their interpretation that apoC-III rapidly and completely exchanges between lipoproteins is by inference only and not by direct measurement. One possibility is that enrichment curves could reflect an average of several distinctly different apoC-III pools within VLDL or HDL (which is incidentally the case for VLDL apoB and for HDL apoA-I when it is isolated and analyzed as one fraction). The pattern of apoC-III distribution within triglyceride-rich lipoproteins certainly does not suggest a random equilibration of apoC-III. ApoC-III-immunoaffinity chromatography separation of VLDL has demonstrated that VLDL containing apoC-III have as many as 100 apoC-III molecules per particle, yet a significant portion of VLDL do not contain apoC-III at all (4Khoo C. Campos H. Judge H. Sacks F.M. Effects of estrogenic oral contraceptives on the lipoprotein B particle system defined by apolipoproteins E and C-III content.J. Lipid Res. 1999; 40: 202-212Abstract Full Text Full Text PDF PubMed Google Scholar, 26Zheng C. Khoo C. Furtado J. Ikewaki K. Sacks F.M. Dietary monounsaturated fat activates metabolic pathways for triglyceride-rich lipoproteins that involve apolipoproteins E and C-III.Am. J. Clin. Nutr. 2008; 88: 272-281Crossref PubMed Scopus (42) Google Scholar). Another problem with the one-pool concept for plasma apoC-III metabolism is that it fails to explain the asymmetrical presence of apoC-III among triglyceride-rich lipoproteins and HDL. ApoC-III is present across the entire spectrum of differently-sized plasma lipoproteins from large VLDL to small HDL. However, apoC-III is present on only 30–70% of VLDL, a smaller percentage of IDL, 5–15% of LDL, and a minority of HDL particles. The actual apoC-III distribution pattern, as demonstrated in Fig. 1, suggests that apoC-III transfer between various lipoproteins is a regulated process and requires other factors. If apoC-III is freely and rapidly exchangeable in a single pool, then exchange would be restricted to apoC-III-containing lipoprotein subtypes. This would require an unknown property of apoC-III-containing lipoproteins that permitted apoC-III to transfer freely among them and not to nonapoC-III containing lipoproteins. Therefore, an unanswered question that needs to be resolved is the extent to which apoC-III exchanges between VLDL and HDL. Although some studies have demonstrated exchange and equilibration of apoC-III between VLDL and HDL (24Nguyen M.N. Chan D.C. Dwyer K.P. Bolitho P. Watts G.F. Barrett P.H. Use of Intralipid for kinetic analysis of HDL apoC-III: evidence for a homogeneous kinetic pool of apoC-III in plasma.J. Lipid Res. 2006; 47: 1274-1280Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 27Huff M.W. Fidge N.H. Nestel P.J. Billington T. Watson B. Metabolism of C-apolipoproteins: kinetics of C–II, C–III1 and C–III2, and VLDL-apolipoprotein B in normal and hyperlipoproteinemic subjects.J. Lipid Res. 1981; 22: 1235-1246Abstract Full Text PDF PubMed Google Scholar), others have found nonexchangeable pools of apoC-III that do not completely equilibrate between VLDL and HDL (11Batal R. Tremblay M. Barrett P.H. Jacques H. Fredenrich A. Mamer O. Davignon J. Cohn J.S. Plasma kinetics of apoC-III and apoE in normolipidemic and hypertriglyceridemic subjects.J. Lipid Res. 2000; 41: 706-718Abstract Full Text Full Text PDF PubMed Google Scholar, 28Bukberg P.R. Le N.A. Ginsberg H.N. Gibson J.C. Rubinstein A. Brown W.V. Evidence for non-equilibrating pools of apolipoprotein C-III in plasma lipoproteins.J. Lipid Res. 1985; 26: 1047-1057Abstract Full Text PDF PubMed Google Scholar). Based on in vitro experiments, Boyle et al. (29Boyle K.E. Phillips M.C. Lund-Katz S. Kinetics and mechanism of exchange of apolipoprotein C-III molecules from very low density lipoprotein particles.Biochim. Biophys. Acta. 1999; 1430: 302-312Crossref PubMed Scopus (15) Google Scholar) found two kinetic pools of apoC-III that transferred between VLDL and HDL at different speeds. ApoC-III in the fast pool rapidly transferred from donor to recipient lipoproteins in a matter of minutes, whereas apoC-III in the slow pool followed a monoexponential rate of exchange with a t1/2 of 3 h. The distribution of apoC-III between fast and slow pools was variable but apparently depended on the size of the donor particles. These results suggest that the two kinetically distinct pools may be related to conformational changes in individual apoC-III molecules on the lipoprotein surface. In a separate study, labeled apoC-III disappearance from plasma was found to follow tri-exponential kinetics, and differences in plasma and urine radioactivity curves suggested the presence of kinetically distinct pools of apoC-III (30Malmendier C.L. Lontie J.F. Grutman G.A. Delcroix C. Metabolism of apolipoprotein C-III in normolipemic human subjects.Atherosclerosis. 1988; 69: 51-59Abstract Full Text PDF PubMed Scopus (26) Google Scholar). These findings for apoC-III are analogous to the properties of apoE, which is a fixed and exchangeable component within VLDL of various sizes (31Gianturco S.H. Gotto Jr, A.M. Bradley W.A. Hypertriglyceridemia: lipoprotein receptors and atherosclerosis.Adv. Exp. Med. Biol. 1985; 183: 47-71PubMed Google Scholar). Our tracer studies of apoB metabolism have shown that apoC-III-containing VLDL and IDL are converted to VLDL, IDL, and LDL without apoC-III (8Zheng C. Khoo C. Ikewaki K. Sacks F.M. Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions.J. Lipid Res. 2007; 48: 1190-1203Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 9Zheng C. Khoo C. Furtado J. Sacks F.M. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype.Circulation. 2010; 121: 1722-1734Crossref PubMed Scopus (184) Google Scholar). More than half of apoC-III-containing VLDL and IDL follow this pathway, losing their triglyceride content together with apoC-III. They are thus transformed into slowly turning over lipoproteins that do not contain apoC-III. Partial loss of apoC-III also happens to triglyceride-rich lipoproteins with apoC-III as evidenced by their diminishing apoC-III content as they become smaller (26Zheng C. Khoo C. Furtado J. Ikewaki K. Sacks F.M. Dietary monounsaturated fat activates metabolic pathways for triglyceride-rich lipoproteins that involve apolipoproteins E and C-III.Am. J. Clin. Nutr. 2008; 88: 272-281Crossref PubMed Scopus (42) Google Scholar). It remains to be studied whether apoC-III molecules released from VLDL and IDL are relocated to other apoB lipoproteins or HDL or are cleared from circulation directly. Similarly, it is not entirely clear what processes regulate the transfer of apoC-III from HDL to VLDL. Although apoC-III can readily transfer from HDL to VLDL or chylomicron-sized lipid emulsions (24Nguyen M.N. Chan D.C. Dwyer K.P. Bolitho P. Watts G.F. Barrett P.H. Use of Intralipid for kinetic analysis of HDL apoC-III: evidence for a homogeneous kinetic pool of apoC-III in plasma.J. Lipid Res. 2006; 47: 1274-1280Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 30Malmendier C.L. Lontie J.F. Grutman G.A. Delcroix C. Metabolism of apolipoprotein C-III in normolipemic human subjects.Atherosclerosis. 1988; 69: 51-59Abstract Full Text PDF PubMed Scopus (26) Google Scholar), in our tracer studies, we have not found evidence in vivo for acquisition of apoC-III by circulating VLDL that do not yet have apoC-III. It is possible that if indeed apoC-III does move from HDL to VLDL in significant amounts, the preferred recipient VLDL are the large particles that already possess considerable amounts of apoC-III. One additional reason to question the simplicity of a one-pool model of plasma apoC-III metabolism is that apoC-III exists as three isoforms, i.e., apoC-III0, apoC-III1 and apoC-III2, corresponding to 0-2 sialic acid molecules on the protein. The isoform with most sialic acid, apoC-III2, tends to have a higher FCR compared with monosialylated apoC-III1, and apoC-III0, the less-predominant isoform, has a significantly slower FCR and lower production rates compared with the other two isoforms (32Mauger J.F. Couture P. Bergeron N. Lamarche B. Apolipoprotein C-III isoforms: kinetics and relative implication in lipid metabolism.J. Lipid Res. 2006; 47: 1212-1218Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). These data suggest heterogeneity among apoC-III isoforms, regarding both secretion and clearance, which should be taken into consideration when dealing with disease conditions that directly affect apoC-III sialyation, including chronic renal failure (33Holdsworth G. Stocks J. Dodson P. Galton D.J. An abnormal triglyceride-rich lipoprotein containing excess sialylated apolipoprotein C-III.J. Clin. Invest. 1982; 69: 932-939Crossref PubMed Scopus (54) Google Scholar). Current modeling of apoC-III kinetic data has assumed that apoC-III is secreted on both VLDL and HDL, and that the distribution of secretion is proportional to their respective pool sizes. However, it is not clear if this assumption is correct. Recent experiments with hepatocytes expressing apoC-III show that the vast majority of apoC-III is found on HDL instead of VLDL in the media of cultured cells (10Sundaram M. Zhong S. Khalil M.B. Links P.H. Zhao Y. Iqbal J. Hussain M.M. Parks R.J. Wang Y. Yao Z. Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions.J. Lipid Res. 2010; 51: 150-161Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). It is unclear whether apoC-III is secreted together with HDL or if HDL acquires apoC-III after secretion. On the other hand, the same group reported that apoC-III seemed to play an important role in packaging lipids onto VLDL precursors (10Sundaram M. Zhong S. Khalil M.B. Links P.H. Zhao Y. Iqbal J. Hussain M.M. Parks R.J. Wang Y. Yao Z. Expression of apolipoprotein C-III in McA-RH7777 cells enhances VLDL assembly and secretion under lipid-rich conditions.J. Lipid Res. 2010; 51: 150-161Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 34Sundaram M. Zhong S. Bou Khalil M. Zhou H. Jiang Z.G. Zhao Y. Iqbal J. Hussain M.M. Figeys D. Wang Y. Functional analysis of the missense APOC3 mutation Ala23Thr associated with human hypotriglyceridemia.J. Lipid Res. 2010; 51: 1524-1534Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Indeed, the majority of apoC-III in the microsomal lumen was found associated with IDL-sized lipid droplets, which later fused with VLDL precursors to form VLDL. Therefore, it is possible that apoC-III is secreted as an integral component of lipoproteins and is not a result of random acquisition by acceptor particles. Once again, apoC-III appears to have a specific and not simply a random role in regulating VLDL production by the liver. In conclusion, it is our opinion that: 1) hepatic apoC-III production (i.e., synthesis and secretion) plays an important role in determining the size or number of triglyceride-rich VLDL secreted by the liver; 2) in the blood, different lipoproteins (whether apoB- or apoA-I-containing) have different numbers of apoC-III molecules, which may be determined by the structure or composition of the lipoproteins themselves; and 3) irrespective of whether all apoC-III is exchangeable or not, it significantly affects the metabolism of the particle on which it resides, and in so doing, plays a central role in determining the concentration in the circulation of potentially atherogenic VLDL, IDL, and small dense LDL.

A number of different food components are known to reduce plasma and LDL-cholesterol levels by affecting intestinal cholesterol absorption. They include: soluble fibers, phytosterols, saponins, phospholipids, soy protein and stearic acid. These compounds inhibit cholesterol absorption by affecting cholesterol solubilization in the intestinal lumen, interfering with diffusion of luminal cholesterol to the gut epithelium and/or inhibiting molecular mechanisms responsible for cholesterol uptake by the enterocyte. Cholesterol content of intestinal chylomicrons is subsequently reduced, less cholesterol is transported to the liver within chylomicron remnants, hepatic LDL-receptor activity is increased and plasma levels of LDL-cholesterol are decreased. Reduced hepatic VLDL production and less conversion of VLDL to LDL also contribute to lower LDL levels. Certain food components may also affect intestinal bile acid metabolism. Further investigation of the way in which these functional ingredients affect intestinal lipid metabolism will facilitate their use and application as cardiovascular nutraceuticals.

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