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Clinical Case A 45-year-old woman presented to the emergency department with weakness and was found to have a Hb level of 68 g/l. She was also tachycardic (pulse 118 x/min) and hypertensive with a BP of 210/108 mmhg. She had a history of ulcerative colitis, menorrhagia and seronegative arthritis for which she had been using 5mg prednisolone daily for several years. The patient had suffered and episode of heart failure 4 years earlier of unknown etiology, during which she was tachycardic, hypertensive and her LVEF was decreased to 35%. In 2016 the patient had undergone an abdominal CT that had shown an incidental finding of a mass in the right adrenal gland, but she did not show up for additional investigations. During the previous year, the patient had developed symptoms of decreased physical fitness, increased weight, livedo reticularis-type skin changes (Figure), agitation, hirsutism and swelling on the neck. Gastroscopy revealed esophageal candidiasis and abdominal CT-scan showed a mass in the right adrenal gland that had increased in size from 2 cm to 3.8 cm compared to the previous CT in 2016 with a density of 21 HU. The patient had clinical Cushing's syndrome, that was confirmed in the lab tests (Table). In addition, lab tests showed an excess production of catecholamines. MRI of the sellar region was performed, that showed a 3×4×3 mm size Rathke's cleft cyst/microadenoma. A CRH stimulation test with inferior petrosal sinus sampling was performed and results were consistent with ectopic ACTH production. The clinical studies were consistent with pheochromocytoma that was also producing ACTH. The patient underwent unilateral adrenalectomy after having been treated with metyrapone and phenoxybenzamine preoperatively. Histopathology was compatible with pheochromcytoma. ACTH staining was negative, but CRH staining was not available. MIB-1 proliferation index was ≤3%. Postoperatively hypercortisolism and catecholamine excess have subsided. The patient has stopped diabetic and antihypertensive medication and she also been cured of the notable livedo reticularis-type skin changes (Figure). Conclusion The clinical presentation of pheochromocytoma in our patient was atypical with coexistence of ACTH-dependent Cushing's syndrome. Furthermore, the patient had a mass in the hypophysis that could have been a potential cause for ACTH-secretion. The clinical and biochemical signs were completely reversed with adrenalectomy, compatible with ectopic Cushing's syndrome due to a pheochromytoma that produced both catecholamines and most probably CRH. In summary pheochromocytomas can rarely also secrete other hormones such as interleukins, calcitonin, ACTH or CRH and this can significantly alter the clinical presentation of both Cushing's syndrome and pheochromocytoma. A recent meta-analysis (Elliott, JCEM 2021) reported 99 published cases of ACTH/CRH-producing pheochromocytomas.

Objective Incretins are known to influence lipid metabolism in the intestine when administered as pharmacologic agents. The aggregate influence of endogenous incretins on chylomicron production and clearance is less clear, particularly in light of opposing effects of co-secreted hormones. Here, we tested the hypothesis that physiological levels of incretins may impact on production or clearances rates of chylomicrons and VLDL. Design and methods A group of 22 overweight/obese men was studied to determine associations between plasma levels of glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) and glucose-dependent insulinotropic polypeptide (GIP) after a fat-rich meal and the production and clearance rates of apoB48- and apoB100-containing triglyceride-rich lipoproteins. Subjects were stratified by above- and below-median incretin response (area under the curve). Results Stratification yielded subgroups that differed about two-fold in incretin response. There were neither differences in apoB48 production rates in chylomicrons or VLDL fractions nor in apoB100 or triglyceride kinetics in VLDL between men with above- vs below-median incretin responses. The men with above-median GLP-1 and GLP-2 responses exhibited higher postprandial plasma and chylomicron triglyceride levels, but this could not be related to altered kinetic parameters. No differences were found between incretin response subgroups and particle clearance rates. Conclusion We found no evidence for a regulatory effect of endogenous incretins on contemporaneous chylomicron or VLDL metabolism following a standardised fat-rich meal. The actions of incretins at pharmacological doses may not be reflected at physiological levels of these hormones.

Background The phospholipase domain-containing 3 gene (PNPLA3)-148M variant is associated with liver steatosis but its influence on the metabolism of triglyceride-rich lipoproteins remains unclear. Here, we investigated the kinetics of large, triglyceride-rich very-low-density lipoprotein (VLDL), (VLDL1), and smaller VLDL2 in homozygotes for the PNPLA3-148M variant. Methods and results The kinetics of apolipoprotein (apo) B100 (apoB100) and triglyceride in VLDL subfractions were analysed in nine subjects homozygous for PNPLA3-148M and nine subjects homozygous for PNPLA3-148I (controls). Liver fat was >3-fold higher in the 148M subjects. Production rates for apoB100 and triglyceride in VLDL1 did not differ significantly between the two groups. Likewise, production rates for VLDL2-apoB100 and -triglyceride, and fractional clearance rates for both apoB100 and triglyceride in VLDL1 and VLDL2, were not significantly different. Conclusions Despite the higher liver fat content in PNPLA3 148M homozygotes, there was no increase in VLDL production. Equally, VLDL production was maintained at normal levels despite the putative impairment in cytosolic lipid hydrolysis in these subjects.

Publisher Copyright: © 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved. Aim: To elucidate the impact of liraglutide on the kinetics of apolipoprotein (apo)B48- and apoB100-containing triglyceride-rich lipoproteins in subjects with type 2 diabetes (T2D) after a single fat-rich meal. Materials and Methods: Subjects with T2D were included in a study to investigate postprandial apoB48 and apoB100 metabolism before and after 16 weeks on l.8 mg/day liraglutide (n = 14) or placebo (n = 4). Stable isotope tracer and compartmental modelling techniques were used to determine the impact of liraglutide on chylomicron and very low-density lipoprotein (VLDL) production and clearance after a single fat-rich meal. Results: Liraglutide reduced apoB48 synthesis in chylomicrons by 60% (p

openaire: EC/H2020/305707/EU//RESOLVE Aims: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. Materials and Methods: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5- 2 H 3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. Results: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). Conclusions: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III.

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 VLDL 1 (very low-density lipoprotein) and VLDL 2 ; and apoB100 in VLDL 1 , VLDL 2 , IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL 1 . In contrast, the fractional catabolic rates of VLDL 2 -apoB100 and VLDL 2 -triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL 2 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 VLDL 2 - and IDL-apoB100 concentrations. Conclusions: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL 1 ) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL 2 , IDL, LDL). Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02948777.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 (TM6SF2) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM65F2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein 13100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VIOL subtractions: large triglyceride-rich VLDL, and smaller, less triglyceride-rich VLDL2. VLDL1-apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise. VLDL,-triglyceride production was 35% lower in the TMSSF2 E167K carriers. In contrast, the direct production rates for VLDL2 apo13100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL1. The impaired secretion of VLDL1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.

Background: \ud Renewed interest in triglyceride-rich lipoproteins as causative agents in cardiovascular disease mandates further exploration of the integrated metabolism of chylomicrons and very low-density lipoproteins (VLDL).\ud \ud Methods: \ud Novel tracer techniques and an integrated multi-compartmental model were used to determine the kinetics of apoB48- and apoB100-containing particles in the chylomicron and VLDL density intervals in 15 subjects with a wide range of plasma triglyceride levels.\ud \ud Results: \ud Following a fat-rich meal, apoB48 appeared in the chylomicron, VLDL1 and VLDL2 fractions in all subjects. Chylomicrons cleared rapidly from the circulation but apoB48-containing VLDL accumulated, and over the day were 3-fold higher in those with high versus low plasma triglyceride. ApoB48-containing particles were secreted directly into both the chylomicron and VLDL fractions at rates that were similar across the plasma triglyceride range studied. During fat absorption, whilst most triglyceride entered the circulation in chylomicrons, the majority of apoB48 particles were secreted into the VLDL density range.\ud \ud Conclusion: \ud The intestine secretes apoB48-containing particles not only as chylomicrons but also directly into the VLDL1 and VLDL2 density ranges both in the basal state and during dietary lipid absorption. Over the day, apoB48-containing particles appear to comprise about 20–25% of circulating VLDL and, especially in those with elevated triglycerides, form part of a slowly cleared ‘remnant’ particle population, thereby potentially increasing CHD risk. These findings provide a metabolic understanding of the potential consequences for increased CHD risk when slowed lipolysis leads to the accumulation of remnants, especially in individuals with hypertriglyceridemia.

Supplemental Digital Content is available in the text., Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.

Background Overconsumption of dietary sugars, fructose in particular, is linked to cardiovascular risk factors such as type 2 diabetes, obesity, dyslipidemia and nonalcoholic fatty liver disease. However, clinical studies have to date not clarified whether these adverse cardiometabolic effects are induced directly by dietary sugars, or whether they are secondary to weight gain. Objectives To assess the effects of fructose (75 g day−1), served with their habitual diet over 12 weeks, on liver fat content and other cardiometabolic risk factors in a large cohort (n = 71) of abdominally obese men. Methods We analysed changes in body composition, dietary intake, an extensive panel of cardiometabolic risk markers, hepatic de novo lipogenesis (DNL), liver fat content and postprandial lipid responses after a standardized oral fat tolerance test (OFTT). Results Fructose consumption had modest adverse effects on cardiometabolic risk factors. However, fructose consumption significantly increased liver fat content and hepatic DNL and decreased β-hydroxybutyrate (a measure of β-oxidation). The individual changes in liver fat were highly variable in subjects matched for the same level of weight change. The increase in liver fat content was significantly more pronounced than the weight gain. The increase in DNL correlated positively with triglyceride area under the curve responses after an OFTT. Conclusion Our data demonstrated adverse effects of moderate fructose consumption for 12 weeks on multiple cardiometabolic risk factors in particular on liver fat content despite only relative low increases in weight and waist circumference. Our study also indicates that there are remarkable individual differences in susceptibility to visceral adiposity/liver fat after real-world daily consumption of fructose-sweetened beverages over 12 weeks.

Background and aims: Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. Methods and results: As many as 66 obese (BMI 26-40 kg/m(2)) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). Conclusion: In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge. (C) 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

BackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95thpercentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

Background We asked whether, after excluding familial hypercholesterolemia, individuals with high low‐density lipoprotein cholesterol ( LDL ‐C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population‐based hyperlipidemias. Methods and Results We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first‐degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias ( LDL ‐C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta‐analysis of the hyperlipidemic families and the population cohort (high LDL ‐C: hazard ratio, 1.74 [95% CI, 1.48–2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09–1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid‐lowering medication. In lipidomic profiling, high LDL ‐C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P ‐value range 0.038–2.3×10 −56 ). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population ( LDL ‐C: r =0.80; triacylglycerides: r =0.96; no lipid species deviated between the cohorts). Conclusions Hyperlipidemias with family history conferred similar coronary artery disease risk as population‐based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL ‐C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population‐ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

AimGenetic investigation of human plasma lipidome to get insights into lipid-related disorders beyond traditional lipid measures.Methods and ResultsWe performed a genome-wide association study (GWAS) of 141 lipid species (n=2,181 individuals), followed by phenome-wide scans (PheWAS) with 44 clinical endpoints related to cardiometabolic, psychiatric and gastrointestinal disorders (n=456,941 individuals). SNP-based heritability for lipid species ranged from 0.10-0.54. Lipids with long-chain polyunsaturated fatty acids showed higher heritability and genetic sharing, suggesting considerable genetic regulation at acyl chains levels. We identified 35 genomic regions associated with at least one lipid species (P−8), revealing 37 new SNP-lipid species pair associations e.g. new association between ABCG5/8 and CE(20:2;0). PheWAS of lipid-species-associated loci suggested new associations of BLK with obesity, FADS2 with thrombophlebitis, and BLK and SPTLC3 with gallbladder disease (false discovery rate SYNGR1, MIR100HG, and PTPRN2 in desaturation and/or elongation of fatty acids. At known lipid loci (FADS2, APOA5 and LPL), genetic associations provided detailed insights to their roles in lipid biology and diseases. We also show that traditional lipid measures may fail to capture lipids such as lysophospatidylcholines (LPCs) and phosphatidylcholines (PCs) that are potential disease risk factors, but are not included in routine screens. The full genome-wide association statistics are available on the web-based database (http://35.205.141.92).ConclusionOur study reveals genetic regulation of plasma lipidome and highlights the potential of lipidomic profiling in disease gene mapping.

Aims Patients with type 2 diabetes and non‐alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon‐like peptide 1 (GLP‐1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single‐blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high‐fat mixed meal were measured before and at the end of the liraglutide intervention. Results Weight loss at Week 16 was similar between the groups: −2.4 kg (−2.5%) in the liraglutide group and −2.1 kg (−2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or β‐hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.

Aims: To characterize and compare coronary artery disease (CAD) risk and detailed lipidomic profiles of individuals with familial and population-ascertained hyperlipidemias.Methods and Results: We determined incident CAD risk for 760 members of 66 hyperlipidemic families (≥ 2 first degree relatives with the same hyperlipidemia) and 19,644 Finnish FINRISK population study participants. We also quantified 151 lipid species in plasma or serum samples from 550 members of 73 hyperlipidemic pedigrees and 897 FINRISK participants using a mass spectrometric shotgun lipidomics platform. Hyperlipidemias (LDL-C or triacylglycerides over 90th population percentile) were associated with increased CAD risk (high LDL-C: HR 1.74, 95% CI 1.48–2.04; high triacylglycerides: HR 1.38, 95% CI 1.09–1.74) and the risk estimates were very similar between the family and population samples. High LDL-C was associated with altered levels of 105 lipid species in families (p-value range 0.033–7.3*10−20 at 5% false discovery rate) and 51 species in the population samples (p-value range 0.017–6.8*10−21). Hypertriglyceridemia was associated with altered levels of 117 lipid species in families (p-value range 0.035–1.8*10−49) and 119 species in the population sample (p-value range 0.038–2.3*10−56). The lipidomics profiles of hyperlipidemias were highly similar in families and population samples.Conclusion: We identified distinct lipidomic profiles associated with high LDL-C and triacylglyceride levels. CAD risk, lipidomic profiles and genetic profiles are highly similar between familial and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms. Our results do not support different screening and treatment for such hyperlipidemias.

A carbohydrate-restricted diet is a widely recommended intervention for non-alcoholic fatty liver disease (NAFLD), but a systematic perspective on the multiple benefits of this diet is lacking. Here, we performed a short-term intervention with an isocaloric low-carbohydrate diet with increased protein content in obese subjects with NAFLD and characterized the resulting alterations in metabolism and the gut microbiota using a multi-omics approach. We observed rapid and dramatic reductions of liver fat and other cardiometabolic risk factors paralleled by (1) marked decreases in hepatic de novo lipogenesis; (2) large increases in serum beta-hydroxybutyrate concentrations, reflecting increased mitochondrial beta-oxidation; and (3) rapid increases in folate-producing Streptococcus and serum folate concentrations. Liver transcriptomic analysis on biopsy samples from a second cohort revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways. Our results highlight the potential of exploring diet-microbiota interactions for treating NAFLD. QC 20180404

Objectives— Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL 1 ) triglycerides. Approach and Results— A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL 1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate ( r =0.44, P r =0.45, P r =0.49, P r =0.55, P 1 -triglycerides and VLDL 1 -apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL 1 -triglycerides ( r =0.56, P 1 -apoB ( r =0.53, P 1 -triglycerides ( r =0.48, P 1 -apoB ( r =0.51, P Conclusions— Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL 1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

Background Cytomegalovirus (CMV) remains an important pathogen in solid organ transplant patients. Objective We executed a hybrid prophylactic and pre-emptive valganciclovir (VGCV) prophylaxis to prevent CMV infection in heart transplant patients with anti-thymocyte globulin (ATG) induction and retrospectively evaluated the efficacy and safety of this regimen. Methods Hundred adult heart transplant patients between 2004 and 2010 were included. Recipients with CMV serostatus D+/R- received VGCV 900 mg OD for 6 months and 94.2% (81/86) of R+ recipients received a low-dose 450 mg OD for 3 months. Blood CMV was monitored until 3 months after cessation of the prophylaxis. Results All patients accomplished the prophylaxis. The overall incidence of CMV disease was 4% (4/100) and it was more frequent in D+/R- patients (P = .001). Three of eighty-six (3.5%) of R+ patients had CMV infection (one CMV disease) while on prophylaxis, 2/3 were still on the original significantly reduced renal dose though. There was one late CMV disease in both D+/R- and R+ groups. Ganciclovir/VGCV treatment was successful in all patients. Conclusions The hybrid strategy with low-dose VGCV in R+ patients with ATG was efficient and safe. The good treatment results indicate that the regimen did not lead to a clinically relevant resistance. Optimal renal dosage is essential throughout prophylaxis.

Background and aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). Methods: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). Results: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (

ObjectivePostprandial hypertriglyceridemia is an important risk factor for cardiovascular disease. The mechanisms are still unclear. Here it was tested if hepatic de novo lipogenesis (DNL) and lipid oxidation influence the postprandial responses of triglyceride-rich lipoproteins (TRL) in humans. MethodsThe contribution of hepatic DNL to hepatic TRL production was analyzed in 67 men and women with a moderate range of BMI after a fat-rich meal. Also, lipase activities, liver fat, and 3-OH-butyrate were quantitated as an indicator of -oxidation. Lipoproteins and metabolic markers were measured in fasting and postprandial blood samples. ResultsPostprandial DNL correlates with postprandial TG and apolipoprotein (apo) C-III responses in plasma and with TG, apoB48 and apoB100 responses in TRLs and their larger remnant particles. Fasting and 8-h postprandial DNL was inversely related to 3-OH-butyrate but not to liver fat content. Fasting apoC-III and 3-OH-butyrate, but not liver fat, independently predicted fasting DNL. ConclusionsThe fasting and 8-h postprandial rate of DNL was inversely associated with the hepatic lipid oxidation in humans. DNL contributes significantly to the TG content in TRLs but not to the amount of liver fat, suggesting that an imbalance between DNL and fat oxidation contributes to postprandial atherogenic dyslipidemia.

Familial hyperlipidemias including but not limited to familial hypercholesterolemia (FH) are often evaluated distinctly from population-based hyperlipidemias. We asked whether this practice is warranted either by greater coronary artery disease (CAD) risk or by different detailed lipid profiles in

Hyperlipidemia, particularly high LDL-C or TG, is the most important heritable risk factor for coronary artery disease (CAD). Its most severe form, monogenic familial hypercholesterolemia (FH) increases CAD risk more than expected from a single LDL-C measurement, likely due to lifelong cumulative

Objective— Low high-density lipoprotein cholesterol (HDL-C) is associated with cardiometabolic pathologies. In this study, we investigate the biological pathways and individual genes behind low HDL-C by integrating results from 3 high-throughput data sources: adipose tissue transcriptomics, HDL lipidomics, and dense marker genotypes from Finnish individuals with low or high HDL-C (n=450). Approach and Results— In the pathway analysis of genetic data, we demonstrate that genetic variants within inflammatory pathways were enriched among low HDL-C associated single-nucleotide polymorphisms, and the expression of these pathways upregulated in the adipose tissue of low HDL-C subjects. The lipidomic analysis highlighted the change in HDL particle quality toward putatively more inflammatory and less vasoprotective state in subjects with low HDL-C, as evidenced by their decreased antioxidative plasmalogen contents. We show that the focal point of these inflammatory pathways seems to be the HLA region with its low HDL-associated alleles also associating with more abundant local transcript levels in adipose tissue, increased plasma vascular cell adhesion molecule 1 (VCAM1) levels, and decreased HDL particle plasmalogen contents, markers of adipose tissue inflammation, vascular inflammation, and HDL antioxidative potential, respectively. In a population-based look-up of the inflammatory pathway single-nucleotide polymorphisms in a large Finnish cohorts (n=11 211), no association of the HLA region was detected for HDL-C as quantitative trait, but with extreme HDL-C phenotypes, implying the presence of low or high HDL genes in addition to the population-genomewide association studies–identified HDL genes. Conclusions— Our study highlights the role of inflammation with a genetic component in subjects with low HDL-C and identifies novel cis -expression quantitative trait loci ( cis -eQTL) variants in HLA region to be associated with low HDL-C.

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined., Author Summary Familial combined hyperlipidemia (FCH) is a familial dyslipidemia and the most common familial risk factor for premature coronary heart disease. Its genetic architecture is poorly understood. Rare high-impact variants have been identified in some patients, but have not explained a substantial portion of the trait. FCH has previously been speculated to be a polygenic disorder, but genetic data supporting this hypothesis have so far been incomplete. We provide experimental evidence for the polygenicity and heterogeneity of FCH in a large set of affected families using comprehensive genome-wide variant data. Approximately a third of the affected FCH individuals in our sample had high polygenic burden, and only a minority carried high-impact variants identifiable by genotyping. We show that the polygenic burden of affected FCH family members is comparable to that observed in individuals with similar lipid phenotypes in the general population. Genetic variants identified in large-scale population studies can also underlie the typical phenotypes observed in complex familial diseases such as FCH. Advances in genetic diagnosis based on population samples may thus also benefit FCH families. Families without high polygenic burden are good candidates for sequencing studies to identify rare variants not observable with genotyping.

IF 5.531; International audience; Context: The metabolism of high-density lipoprotein (HDL) is severely impaired in individuals with abdominal obesity. However, the specific metabolism of apolipoprotein (apo)-A-II, the second major apolipoprotein of HDL, remains poorly known. The relationships between HDL apoA-II catabolism and other metabolic variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, remain to be investigated.Objectives: Our aim was to study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I.Design: We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity.Results: In a univariate analysis, apoA-II FCR was positively correlated with body mass index, sc fat, liver fat, apoA-I FCR, apoA-I production rate (PR), apoA-II pool, apoA-II PR, VLDL1-triglyceride PR, VLDL2-triglyceride PR, VLDL2-triglyceride (TG) FCR, and VLDL2-apoB FCR and negatively with HDL cholesterol to apoA-I ratio. After adjustment for apoA-I FCR, a strong positive correlation between apoA-II FCR and VLDL1-TG indirect FCR was observed (r = 0.520, P < .0001). In a multivariate analysis, apoA-II FCR was independently and positively associated with apoA-I FCR (P < .0001) and VLDL1-TG indirect FCR (P < .0001). Both variables explained 59.7% of the variability in apoA-II FCR.Conclusions: We show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR. These data suggest that, in a condition of delayed VLDL1 catabolism, such as abdominal obesity, retention of apoA-II in the VLDL1 pool may occur, with an effect on apoA-II catabolism. The consequences of this link between VLDL1 catabolism and apoA-II catabolism remain to be determined.

Context Glucose and lipids stimulate the gut-hormones glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) but the effect of these on human postprandial lipid metabolism is not fully clarified. Objective To explore the responses of GLP-1, GLP-2 and GIP after a fat-rich meal compared to the same responses after an oral glucose tolerance test (OGTT) and to investigate possible relationships between incretin response and triglyceride-rich lipoprotein (TRL) response to a fat-rich meal. Design Glucose, insulin, GLP-1, GLP-2 and GIP were measured after an OGTT and after a fat-rich meal in 65 healthy obese (BMI 26.5-40.2 kg/m(2)) male subjects. Triglycerides (TG), apoB48 and apoB100 in TG-rich lipoproteins (chylomicrons, VLDL1 and VLDL2) were measured after the fat-rich meal. Main Outcome Measures Postprandial responses (area under the curve, AUC) for glucose, insulin, GLP-1, GLP-2, GIP in plasma, and TG, apoB48 and apoB100 in plasma and TG-rich lipoproteins. Results The GLP-1, GLP-2 and GIP responses after the fat-rich meal and after the OGTT correlated strongly (r = 0.73, p

Objective To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs. Methods Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and triglycerides in the very low-density lipoprotein 1 and 2 (VLDL1 and VLDL2) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and triglycerides in the chylomicron, VLDL1 and VLDL2 fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting. Results Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL1 particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial triglycerides with less accumulation of apoB100 in the VLDL1 fraction and a faster transfer of apoB100 into the VLDL2 fraction. In contrast, fasting VLDL1 secretion does not predict postprandial triglyceride accumulation. Conclusions Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis.

Objective— Obesity increases the risk of cardiovascular disease and premature death. However, not all obese subjects develop the metabolic abnormalities associated with obesity. The aim of this study was to clarify the mechanisms that induce dyslipidemia in obese subjects. Methods and Results— Stable isotope tracers were used to elucidate the pathophysiology of the dyslipidemia in hypertriglyceridemic ( n =14) and normotriglyceridemic ( n =14) obese men (with comparable body mass index and visceral fat volume) and in normotriglyceridemic nonobese men ( n =10). Liver fat was determined using proton magnetic resonance spectroscopy, and subcutaneous abdominal and visceral fat were measured by magnetic resonance imaging. Serum triglycerides in obese subjects were increased by the combination of increased secretion and severely impaired clearance of triglyceride-rich very-low-density lipoprotein 1 particles. Furthermore, increased liver and subcutaneous abdominal fat were linked to increased secretion of very-low-density lipoprotein 1 particles, whereas increased plasma levels of apolipoprotein C-III were associated with impaired clearance in obese hypertriglyceridemic subjects. Conclusion— Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects with similar levels of visceral adiposity. The results emphasize the clinical importance of assessing hypertriglyceridemic waist in obese subjects to identify subjects at high cardiometabolic risk.

The metabolic syndrome (MetS) pandemic predisposes patients to low high-density lipoprotein cholesterol (HDL-C). To successfully treat low HDL-C, there is an urgent need for a better understanding of the changes in HDL particles in the low-HDL-C state. Especially, apolipoprotein (apo) E metabolism in HDL particles is an emerging and important issue. Therefore, we determined HDL subspecies, apo E distribution, and the impact of the MetS in subjects with low and high HDL-C. We studied 246 subjects derived from the Finnish Health 2000 Health Examination Survey. The 2 groups included 113 low-HDL-C (≤10th percentile) and 133 high-HDL-C (≥90th percentile) subjects. The low-HDL-C subjects had higher apo E concentration (39.4 ± 19.4 vs 25.6 ± 8.0 μg/mL, P < .001) and smaller HDL mean particle size (9.0 ± 0.2 vs 9.8 ± 0.3 nm, P < .001). The distribution of apo E genetic isoforms could not explain the difference. Apolipoprotein E content of very low-density lipoprotein particles was comparable between the study groups. In the low-HDL-C subjects, apo E level in large HDL particles was lower (P < .001) compared with that in the high-HDL-C subjects. The subjects with MetS had smaller HDL mean particle size and higher serum apo E concentration. Serum apo E concentration associated positively with different MetS markers (waist circumference, triglycerides, and glucose), whereas HDL mean particle size associated with those negatively. Our results highlight that, in the low-HDL-C state, there are changes in the size and composition of HDL particles associating with MetS. Apolipoprotein E, although generally considered antiatherogenic, associates with MetS and low HDL-C. Our results emphasize the need for a better understanding of apo E metabolism in HDL particles.

The aim of this study was to investigate the use of 1H-MRS with various echo times to characterize subcutaneous human adipose tissue (SAT) triglyceride composition and to validate the findings with fatty acid (FA) analysis of SAT biopsies by gas chromatography (GC). 1H-MRS spectra were acquired with a 1.5 Tesla clinical imager from the SAT of 17 healthy volunteers, with 10 undergoing SAT biopsy. Spectra were localized with PRESS and a series of echo times; 30,50,80,135,200,300 and 540 ms were acquired with TR = 3000 ms. Prior knowledge from phantom measurements was used to construct AMARES fitting models for the lipid spectra. SAT FA composition were compared with serum lipid levels and subject characteristics in 17 subjects. Long TE (135,200 ms) spectra corresponded better with the GC data than short TE (30,50 ms) spectra. TE = 135 ms was found optimal for determining diallylic content (R = 0.952, p

The main antiatherogenic function of HDL is to promote the efflux of cholesterol from peripheral cells and transport it to the liver for excretion in a process termed reverse cholesterol transport. The aim of this study was to evaluate the cholesterol efflux capacity in low- and high-HDL subjects by utilizing monocytes and serum from 18 low-HDL and 15 high-HDL subjects. Low and high HDL levels were defined, respectively, as HDLor =10(th) and HDLor =90(th) Finnish age/sex-specific percentile. Cholesterol efflux from [(3)H]cholesterol-oleate-acetyl-LDL-loaded monocyte-derived macrophages to standard apolipoprotein A-I (apoA-I), HDL(2), and serum was measured. In addition, cholesterol efflux from acetyl-LDL-loaded human THP-1 macrophages to individual sera (0.5%) derived from the study subjects was evaluated. Cholesterol efflux to apoA-I, HDL(2), and serum from macrophage foam cells derived from low- and high-HDL subjects was similar. The relative ABCA1 and ABCG1 mRNA expression levels in unloaded macrophages, as well as their protein levels in loaded macrophage foam cells, were similar in the two study groups. Cholesterol efflux from THP-1 foam cells to serum recovered from high-HDL subjects was slightly higher than that to serum from low-HDL subjects (P = 0.046). Cholesterol efflux from THP-1 macrophages to serum from study subjects correlated with serum apoB (P = 0.033), apoA-I (P = 0.004), apoA-II (P0.0001), and the percentage of apoA-I present in the form of prebeta-HDL (P = 0.0001). Our data reveal that macrophages isolated from either low- or high-HDL subjects display similar cholesterol efflux capacity to exogenous acceptors. However, sera from low-HDL subjects have poorer cholesterol acceptor ability as compared with sera from high-HDL subjects.

HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.