nutrients Article Decreased Efficiency of Very-Low-Density Lipoprotein Lipolysis Is Linked to Both Hypertriglyceridemia and Hypercholesterolemia, but It Can Be Counteracted by High-Density Lipoprotein Ewa Wieczorek * , Agnieszka Cwikli´ ´nska , Agnieszka Kuchta, Barbara Kortas-Stempak, Anna Gliwi ´nskaand Maciej Jankowski Department of Clinical Chemistry, Faculty of Pharmacy, Medical University of Gda´nsk,80-210 Gda´nsk,Poland; [email protected] (A.C.);´ [email protected] (A.K.); [email protected] (B.K.-S.); [email protected] (A.G.); [email protected] (M.J.) * Correspondence: [email protected]; Tel.: +48-58-349-2777 Abstract: Impaired triglyceride-rich lipoprotein plasma catabolism is considered the most important factor for hypertriglyceridemia development. The aim of this study was to evaluate the impact of hypercholesterolemia and hypertriglyceridemia on the efficiency of lipoprotein lipase (LPL)- mediated very-low-density lipoprotein (VLDL)-triglyceride lipolysis and the role of high-density Citation: Wieczorek, E.; Cwikli´nska,´ lipoprotein (HDL) in this process. Subjects with no history of cardiovascular disease (CVD) and A.; Kuchta, A.; Kortas-Stempak, B.; untreated with lipid-lowering agents were recruited into the study and divided into normolipidemic, Gliwi´nska,A.; Jankowski, M. hypercholesterolemic, and hyperlipidemic groups. VLDL was isolated from serum and incubated Decreased Efficiency of with LPL in the absence or presence of HDL. For the hypercholesterolemic and hyperlipidemic groups, Very-Low-Density Lipoprotein a significantly lower percentage of hydrolyzed VLDL-triglyceride was achieved compared to the Lipolysis Is Linked to Both normolipidemic group (p < 0.01). HDL enhanced the lipolysis efficiency in the hypercholesterolemic Hypertriglyceridemia and Hypercholesterolemia, but It Can Be and hyperlipidemic groups on average by ~7% (p < 0.001). The lowest electrophoretic mobility of the Counteracted by High-Density VLDL remnants indicating the most effective lipolysis was obtained in the normolipidemic group Lipoprotein. Nutrients 2021, 13, 1224. (p < 0.05). HDL presence significantly reduced the electrophoretic mobility of the VLDL remnants for https://doi.org/10.3390/nu13041224 the hypercholesterolemic and hyperlipidemic groups (p < 0.05). The results of our study indicate that VLDL obtained from hypercholesterolemic and hyperlipidemic subjects are more resistant to Academic Editors: John Mamo, lipolysis and are additional evidence of the need for early implementation of hypocholesterolemic Ryu Takechi and Virginie Lam treatment, already in asymptomatic CVD subjects. Received: 26 February 2021 Keywords: high-density lipoprotein; hypercholesterolemia; hypertriglyceridemia; lipolysis; lipopro- Accepted: 6 April 2021 tein lipase; triglycerides; very-low-density lipoprotein Published: 8 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. Cardiovascular disease (CVD) is the leading cause of death worldwide [1]. The major lipid risk factor for CVD development is hypercholesterolemia [2], but accumulating evidence from recent studies shows that an increased triglyceride (TG) level is also strongly associated with cardiovascular morbidity and mortality risk [3]. Hypertriglyceridemia (HTG) occurs in approximately 27% of the population [4] and is Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. closely linked to obesity, considered to be a pandemic of the 21st century [5]. The develop- This article is an open access article ment of HTG can be related to genetic predisposition [6], excessive synthesis, and secretion distributed under the terms and of TG-rich lipoproteins (TRL), including chylomicron (CM) and very-low-density lipopro- conditions of the Creative Commons tein (VLDL) [7], and/or to impaired TRL clearance from plasma [8,9]. Attribution (CC BY) license (https:// Impaired TRL clearance is the most important factor that contributes to the devel- creativecommons.org/licenses/by/ opment of HTG, and the reduced efficiency of intravascular TG hydrolysis mediated by 4.0/). lipoprotein lipase (LPL) is crucial to this process [9]. The impaired clearance leads to a Nutrients 2021, 13, 1224. https://doi.org/10.3390/nu13041224 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, 1224 2 of 12 prolonged presence of TRL remnants in plasma that infiltrate into the subendothelial space, causing inflammation and endothelial dysfunction [10,11]. The increased number of TRL remnants has also been related to the induction of coagulation activity, the generation of highly atherogenic small dense low-density lipoprotein (sdLDL), and an impairment of high-density lipoprotein (HDL) composition and function [6]. HDL plays an important anti-atherogenic role [12], and recent studies show that the beneficial effect of HDL is linked to the functional traits of the lipoprotein rather than its quantity measured with cholesterol content [13]. Plasma TRL and HDL metabolism is closely related [12]: it has been shown that HDL protects the endothelium from the inhibitory effect of VLDL on endothelium-dependent relaxation [14]. The other important mechanism by which HDL may affect TRL metabolism and prevent HTG development and atherosclerosis as a consequence is the interaction between HDL and TRL particles. It has been previously shown that HDL acts as an acceptor of the surface material released from VLDL during LPL-mediated lipolysis, enhancing the efficiency of TG lipolysis. HDL also promotes the conversion of VLDL into IDL/LDL, and the changes in composition and properties of HDL related to metabolic disorders, such as chronic kidney disease, can impair this activity [15]. Since the metabolism of TG and cholesterol are linked due to the shared physicochem- ical properties of the molecules and their presence in the particles of the same lipoprotein classes, there may be a relationship between hypercholesterolemia and HTG development. For instance, it was demonstrated that subjects with familial hypercholesterolemia (FH) with normal fasting TG levels had impaired postprandial TG response to fatty meals com- pared to control, despite similar basal TG levels in FH and control groups [16,17]. Whether the oversecretion and/or impaired TRL catabolism and clearance can be the cause of TRL disturbances and HTG development in hypercholesterolemic subjects is not fully explained and needs to be elucidated [18]. The aim of this study was to evaluate the impact of hypercholesterolemia and hy- pertriglyceridemia on the efficiency of LPL-mediated VLDL lipolysis in subjects with no history of CVD to assess TG-rich lipoprotein metabolism disturbances. The magnitude of the effect of HDL on VLDL lipolysis efficiency was also assessed. We found that similarly to hypertriglyceridemic subjects, the VLDL obtained from hypercholesterolemic subjects with no increased TG serum level had reduced susceptibility to lipolysis compared to controls with normal lipid levels. HDL was able to increase lipolysis efficiency independently on lipid disturbances. 2. Materials and Methods 2.1. Study Groups Forty adults aged 21–59 under the care of the General Practitioner (Non-public Health- Care Center, Pomerania region, Poland) were recruited into the study. Participants were asymptomatic for CVD at the time of recruitment, and a history of a previous cardio- vascular event was excluded. The other detailed study exclusion criteria were: diabetes, liver disease, kidney disease, cancer, asthma, acute disease within 3 months before the study, a treatment course containing lipid-lowering drugs (statins, fibrates, ezetimibe, and PCSK9 inhibitors), hormone replacement therapy (HRT) and other drugs affecting lipid profile (immunosuppressive agents, diuretics, steroids), or heparin. All participants gave written informed consent for participation in the study. The study was approved by the Independent Bioethics Commission for Research of the Medical University of Gdansk, Poland (No. NKBBN/612/2017–2018). Study participants were divided into three groups according to low-density lipopro- tein cholesterol (LDL-C) and TG levels. Namely, LDL-C < 115 mg/dL and TG < 150 mg/dL, the normolipidemic (NL) group; LDL-C ≥ 115 mg/dL and TG < 150 mg/dL, the hyperc- holesterolemic (HC) group; and LDL C ≥ 115 mg/dL and TG ≥ 150 mg/dL, the hyper- lipidemic (HL) group. The characteristics of the study groups are presented in Table1. There were 12 subjects (30%) that were normolipidemic and 28 that had elevated serum Nutrients 2021, 13, 1224 3 of 12 lipid levels. There were 15 patients (38%) who had increased LDL-C levels (HC group) and 13 subjects (32%) who had both increased LDL-C and TG levels (HL group). There were no significant differences in BMI, gender distribution, hypertension, and smoking frequency among the groups. Table 1. Characteristics of study groups and lipid and apolipoprotein levels. Normolipidemic Hypercholesterolemic Hyperlipidemic Parameter p-Value (NL) Group (HC) Group (HL) Group Number 12 15 13 - Age (years) 31 ± 7 40 ±13 41 ± 11 0.050 a BMI (kg/m2) 28 ± 5 28 ± 5 28 ± 4 0.935 a Gender 8/4 (67%/33%) 6/9 (40%/60%) 6/7 (46%/54%) 0.366 c (Female/Male) Hypertension 1 (8%) 5 (33%) 3 (23%) 0.302 c Smoking 3 (25%) 2 (13%) 3 (23%) 0.766 c Serum lipids and apolipoproteins Triglycerides 81 (72–114) 101 (75–135) 164 (151–238) d,e <0.001 b (mg/dL) Total cholesterol 180 (169–188) 215 (197–239) d 240 (210–258)