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Genetic studies of metabolites have identified thousands of variants, many of which are associated with downstream metabolic and obesogenic disorders. However, these studies have relied on univariate analyses, reducing power and limiting context-specific understanding. Here we aim to provide an integrated perspective of the genetic basis of metabolites by leveraging the Finnish Metabolic Syndrome In Men (METSIM) cohort, a unique genetic resource which contains metabolic measurements, mostly lipids, across distinct time points as well as information on statin usage. We increase effective sample size by an average of two-fold by applying the Covariates for Multi-phenotype Studies (CMS) approach, identifying 588 significant SNP-metabolite associations, including 228 new associations. Our analysis pinpoints a small number of master metabolic regulator genes, balancing the relative proportion of dozens of metabolite levels. We further identify associations to changes in metabolic levels across time as well as genetic interactions with statin at both the master metabolic regulator and genome-wide level. Genome-wide association studies of metabolites have revealed hundreds of genetic associations using univariate analyses. Here, the authors use a multivariate approach to perform association analyses for 158 serum metabolites, followed by fine mapping and GxE interaction tests with statin use and age.

Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.

Relationship of Abdominal Visceral and Subcutaneous Adipose Tissue With Lipoprotein Particle Number and Size in Type 2 Diabetes Susan Sam 1 , Steven Haffner 2 , Michael H. Davidson 3 , Ralph B. D'Agostino, Sr. 4 , Steven Feinstein 5 , George Kondos 6 , Alfonso Perez 7 and Theodore Mazzone 1 1 Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, Chicago, Illinois 2 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 3 Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 4 Department of Mathematics, Statistics and Consulting Unit, Boston University, Boston, Massachusetts 5 Department of Medicine, Section of Cardiology, Rush University Medical Center, Chicago, Illinois 6 Department of Medicine, Section of Cardiology, University of Illinois College of Medicine, Chicago, Illinois 7 Takeda Global Research and Development, Deerfield, Illinois Corresponding author: Theodore Mazzone, tmazzone{at}uic.edu Abstract OBJECTIVE— Insulin resistance and type 2 diabetes are associated with an atherogenic lipoprotein profile. We examined the role of visceral and subcutaneous fat depots, independent of BMI, on the dyslipidemia associated with type 2 diabetes. RESEARCH DESIGN AND METHODS— A total of 382 subjects with type 2 diabetes underwent abdominal computed tomography to evaluate subcutaneous (SAT) and visceral adipose tissue (VAT) distribution and had anthropometric measurements to determine BMI and waist and hip circumference. Fasting blood was obtained for lipoprotein particle number and size using nuclear magnetic resonance spectroscopy. The relationship of lipoprotein particle number and size with BMI, SAT, and VAT was examined using multivariable regression models adjusted for age, sex, diabetes therapy, duration of diabetes, smoking, statin use, and A1C levels. The relation of VAT to lipoprotein particle number and size was further evaluated after the addition of BMI, BMI plus SAT, or BMI plus homeostatis is model assessment of insulin resistance (HOMA-IR) to the model. RESULTS— VAT was positively related to VLDL particle number ( P < 0.0001), LDL particle number ( P < 0.01), and VLDL size ( P < 0.0001) and negatively related to LDL size ( P < 0.0001) and HDL size ( P < 0.0001). These relationships remained unchanged after addition of BMI and SAT to the model. After addition of HOMA-IR, VAT remained positively related to VLDL particle number ( P < 0.0001) and size ( P < 0.01) and negatively related to LDL and HDL particle size ( P < 0.0001 for both comparisons). Neither BMI nor SAT was independently related to lipoprotein parameters. CONCLUSIONS— In patients with type 2 diabetes, higher VAT independent of BMI was associated with higher VLDL and LDL particle number, larger VLDL particles, and smaller LDL and HDL particles. This lipoprotein pattern has been associated with increased risk for atherosclerosis and cardiovascular disease. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 9 May 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 4, 2008. Received February 4, 2008. DIABETES

Chronic kidney disease (CKD) induces modifications in lipid and lipoprotein metabolism and homeostasis. These modifications can promote, modulate and/or accelerate CKD and secondary cardiovascular disease (CVD). Lipid and lipoprotein abnormalities — involving triglyceride-rich lipoproteins, LDL and/or HDL — not only involve changes in concentration but also changes in molecular structure, including protein composition, incorporation of small molecules and post-translational modifications. These alterations modify the function of lipoproteins and can trigger pro-inflammatory and pro-atherogenic processes, as well as oxidative stress. Serum fatty acid levels are also often altered in patients with CKD and lead to changes in fatty acid metabolism — a key process in intracellular energy production — that induce mitochondrial dysfunction and cellular damage. These fatty acid changes might not only have a negative impact on the heart, but also contribute to the progression of kidney damage. The presence of these lipoprotein alterations within a biological environment characterized by increased inflammation and oxidative stress, as well as the competing risk of non-atherosclerotic cardiovascular death as kidney function declines, has important therapeutic implications. Additional research is needed to clarify the pathophysiological link between lipid and lipoprotein modifications, and kidney dysfunction, as well as the genesis and/or progression of CVD in patients with kidney disease.Chronic kidney disease (CKD) is associated with alterations in serum lipid profiles that contribute to kidney and cardiovascular disease. Here, the authors examine these changes in serum levels, metabolism and post-translational modifications of lipoproteins and fatty acids that characterize CKD-associated dyslipidaemia.

Diabetic dyslipoproteinemia is characterized by low HDL cholesterol and high triglycerides. We examined the association of lipoprotein particle size and concentration measured by nuclear magnetic resonance (NMR) spectroscopy with clinical type 2 diabetes. This was a prospective study of 26,836 initially healthy women followed for 13 years for incident type 2 diabetes (n = 1,687). Baseline lipids were measured directly and lipoprotein size and concentration by NMR. Cox regression models included nonlipid risk factors (age, race, smoking, exercise, education, menopause, blood pressure, BMI, family history, A1C, and C-reactive protein). NMR lipoproteins were also examined after further adjusting for standard lipids. Incident diabetes was significantly associated with baseline HDL cholesterol, triglycerides, and NMR-measured size and concentration of LDL, IDL, HDL, and VLDL particles. The associations of these particles differed substantially by size. Small LDL(NMR) and small HDL(NMR) were positively associated with diabetes (quintile 5 vs. 1 [adjusted hazard ratios and 95% CIs], 4.04 [3.21-5.09] and 1.84 [1.54-2.19], respectively). By contrast, large LDL(NMR) and large HDL(NMR) were inversely associated (quintile 1 vs. 5, 2.50 [2.12-2.95] and 4.51 [3.68-5.52], respectively). For VLDL(NMR), large particles imparted higher risk than small particles (quintile 5 vs. 1, 3.11 [2.35-4.11] and 1.31 [1.10-1.55], respectively). Lipoprotein particle size remained significant after adjusting for standard lipids and nonlipid factors. In this prospective study of women, NMR lipoprotein size and concentrations were associated with incident type 2 diabetes and remained significant after adjustment for established risk factors, including HDL cholesterol and triglycerides.

In mice, deficiency in the high-density lipoprotein gene T39 stabilizes liver X receptor (LXR), reducing both atherosclerosis and steatohepatitis, suggesting that T39 inhibition could be an effective strategy for reducing these diseases. Anti-atherosclerosic and anti-steatohepatitic Genome-wide association studies have shown that single-nucleotide polymorphisms in the T39 gene, coding for the tetratricopeptide repeat protein 39B, are associated with increased high-density lipoprotein cholesterol levels. Here, Alan Tall and colleagues show in mice that T39 deficiency protects against atherosclerosis through a mechanism that involves stabilization of LXR, a known anti-atherogenic transcription factor. Unlike synthetic LXR ligands, however, T39 deficiency also protects against fatty liver, suggesting that T39 inhibition could be a therapeutic approach to both cardiovascular disease and non-alcoholic fatty liver disease. Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available 1 , are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B ( Ttc39b , C9orf52) ( T39 ), a high-density lipoprotein gene discovered in human genome-wide association studies 2 , promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 ( T39 −/− ) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 ( Abca1 ) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39 −/− mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor ( Ldlr −/− T39 −/− ) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.

In vitro and animal studies have shown positive effects of resveratrol on lipid and lipoprotein metabolism, but human studies specifically designed to examine these effects are lacking. The primary outcome parameter of this study in overweight and slightly obese subjects was the effect of resveratrol on apoA-I concentrations. Secondary outcome parameters were effects on other markers of lipid and lipoprotein metabolism, glucose metabolism, and markers for inflammation and endothelial function. This randomized, placebo-controlled crossover study was conducted in 45 overweight and slightly obese men (n = 25) and women (n = 20) with a mean age of 61 ± 7 years. Subjects received in random order resveratrol (150 mg per day) or placebo capsules for 4 weeks, separated by a 4-week wash-out period. Fasting blood samples were collected at baseline and at the end of each intervention period. Compliance was excellent as indicated by capsule count and changes in resveratrol and dihydroresveratrol concentrations. No difference between resveratrol and placebo was found in any of the fasting serum or plasma metabolic risk markers (mean ± SD for differences between day 28 values of resveratrol vs. placebo: apoA-I; 0.00 ± 0.12 g/L (P = 0.791), apoB100; -0.01 ± 0.11 g/L (P = 0.545), HDL cholesterol; 0.00 ± 0.09 mmol/L (P = 0.721), LDL cholesterol -0.03 ± 0.57 mmol/L (P = 0.718), triacylglycerol; 0.10 ± 0.54 mmol/L (P = 0.687), glucose; -0.08 ± 0.28 mmol/L (P = 0.064), insulin; -0.3 ± 2.5 mU/L (P = 0.516)). Also, no effects on plasma markers for inflammation and endothelial function were observed. No adverse events related to resveratrol intake were observed. 150 mg of daily resveratrol intake for 4 weeks does not change metabolic risk markers related to cardiovascular health in overweight and slightly obese men and women. Effects on glucose metabolism warrant further study. ClinicalTrials.gov NCT01364961.

Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and—not last—to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.

Abstract Background Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering. Content Non–LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events. Summary We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.

Native nanostructured lipoproteins such as low- and high-density lipoproteins (LDL and HDL) are powerful tools for the targeted delivery of drugs and imaging agents. While the cellular recognition of well-known HDL-based carriers occurs via interactions with an HDL receptor, the selective delivery and uptake of LDL particles by target cells are more complex. The most well-known mode of LDL-based delivery is via the interaction between apolipoprotein B (Apo-B) - the main protein of LDL - and the low-density lipoprotein receptor (LDLR). LDLR is expressed in the liver, adipocytes, and macrophages, and thus selectively delivers LDL carriers to these cells and tissues. Moreover, the elevated expression of LDLR in tumor cells indicates a role for LDL in the targeted delivery of chemotherapy drugs. In addition, chronic inflammation associated with hypercholesterolemia (i.e., high levels of endogenous LDL) can be abated by LDL carriers, which outcompete the deleterious oxidized LDL for uptake by macrophages. In this case, synthetic LDL nanocarriers act as 'eat-me' signals and exploit mechanisms of native LDL uptake for targeted drug delivery and imaging. Lastly, recent studies have shown that the delivery of LDL-based nanocarriers to macrophages via fluid-phase pinocytosis is a promising tool for atherosclerosis imaging. Hence, the present review summarizes the use of natural and synthetic LDL-based carriers for drug delivery and imaging and discusses various mechanisms of targeting.