Background: Patients treated with hemodialysis frequently experience cardiovascular complications attributed, among other causes, to dyslipidemia, increased oxidative stress, and inflammation. Objective: The aim of the study was to study the effects of dietary supplementation with concentrated red grape juice (RGJ), a source of polyphenols, on lipoprotein profile, antioxidant capacity, LDL oxidation, and inflammatory biomarkers. Design: Twenty-six patients receiving hemodialysis and 15 healthy subjects were instructed to drink 100 mL RGJ/d for 14 d. Blood was drawn at baseline, twice during RGJ supplementation, and twice during the 6-mo follow-up period. As a control, 12 other randomly recruited hemodialysis patients not receiving RGJ were studied. Lipids, apolipoproteins, oxidized LDL, and antioxidant vitamins were measured in plasma. The bioavailability of RGJ polyphenols was assessed in healthy subjects. Results: The maximum plasma concentration of quercetin was achieved 3 h after RGJ ingestion, which indicates that supplement-derived polyphenols are rapidly absorbed. In both healthy subjects and hemodialysis patients, RGJ consumption increased the antioxidant capacity of plasma without affecting concentrations of uric acid or ascorbic acid; reduced the concentration of oxidized LDL; and increased the concentration of cholesterol-standardized α-tocopherol. RGJ supplementation also caused a significant decrease in LDL-cholesterol and apolipoprotein B-100 concentrations, while increasing the concentrations of HDL cholesterol and apolipoprotein A-I. In a further study in hemodialysis patients, RGJ supplementation for 3 wk significantly reduced plasma monocyte chemoattractant protein 1, an inflammatory biomarker associated with cardiovascular disease risk. Conclusion: Dietary supplementation with concentrated RGJ improves the lipoprotein profile, reduces plasma concentrations of inflammatory biomarkers and oxidized LDL, and may favor a reduction in cardiovascular disease risk.

MicroRNA-148a, whose expression is regulated by the transcription factor SREBP1c, controls LDL and HDL metabolism through direct targeting of the genes encoding the LDL receptor and the cholesterol transporter ABCA1. The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL cholesterol (LDL-C). Whereas the transcriptional regulation of LDLR is well characterized, the post-transcriptional mechanisms that govern LDLR expression are just beginning to emerge. Here we develop a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen we identified and characterized miR-148a as a negative regulator of LDLR expression and activity and defined a sterol regulatory element–binding protein 1 (SREBP1)-mediated pathway through which miR-148a regulates LDL-C uptake. In mice, inhibition of miR-148a increased hepatic LDLR expression and decreased plasma LDL-C. Moreover, we found that miR-148a regulates hepatic expression of ATP-binding cassette, subfamily A, member 1 (ABCA1) and circulating high-density lipoprotein cholesterol (HDL-C) levels in vivo. These studies uncover a role for miR-148a as a key regulator of hepatic LDL-C clearance through direct modulation of LDLR expression and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate an elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.

Lipoprotein metabolism is regulated by the functional interplay between lipoprotein components and the receptors and enzymes with which they interact. Recent evidence indicates that the structurally related glycoproteins CD36 and SR-BI act as cell surface receptors for some lipoproteins. Thus, CD36 has been reported to bind oxidized LDL (OxLDL) and acetylated LDL (AcLDL), while SR-BI also binds native LDL and HDL. The cDNA of human CLA-1 predicts a protein 509 amino acids long that displays a 30% and an 80% amino acid identity with CD36 and mouse or hamster SR-BI, respectively. In this report, we describe the structural characterization of CLA-1 as an 85-kD plasma membrane protein enriched in N-linked carbohydrates. The expression of CLA-1 on mammalian and insect cells has been used to demonstrate that CLA-1 is a high-affinity specific receptor for the lipoproteins HDL, LDL, VLDL, OxLDL, and AcLDL. Northern blot analysis of the tissue distribution of CLA-1 in humans indicated that its expression is mostly restricted to tissues performing very active cholesterol metabolism (liver and steroidogenic tissues). This finding, in the context of the capability of this receptor to bind to both native and modified lipoproteins, strongly suggests that the CLA-1 receptor contributes to lipid metabolism and atherogenesis.

Cholesterol metabolism is tightly regulated at the cellular level and is essential for cellular growth. microRNAs (miRNAs), a class of noncoding RNAs, have emerged as critical regulators of gene ex...